Aqueous ophthalmic solutions of phentolamine and medical uses thereof

ABSTRACT

The invention provides aqueous ophthalmic solutions of phentolamine or pharmaceutically acceptable salts thereof, medical kits, and methods for using such ophthalmic solutions to improve visual performance in a patient. Exemplary aqueous ophthalmic solutions include those containing phentolamine mesylate, mannitol, sodium acetate, and water.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 61/759,530, filed Feb. 1, 2013, the contentsof which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates to aqueous ophthalmic solutions of phentolamine orpharmaceutically acceptable salts thereof, medical kits, and methods forusing such solutions to improve visual performance in a patient.

BACKGROUND

Deficient visual performance can have a significant negative impact on apatient's quality of life, affecting, for example, ability to performnormal daily tasks, perform at school, and perform at work. One type ofvision problem experienced by a substantial number of patients is poornight vision. The inability to see clearly under such low lightconditions can make it difficult and/or dangerous for a patient tooperate a motor vehicle at nighttime. Patients that are more likely toexperience night vision problems include those suffering from nightmyopia, those with an equatorial cortical cataract, and those who havehad surgery to insert an intraocular lens and/or underwent LASIKsurgery. Exemplary symptoms of poor night vision include glare, halos,starburst, ghosting patterns, and/or poor depth perception.

Certain therapies have been described for improving visual performance.For example, the Bernstein Center for Visual Performance offers programsthat utilize visual aids, such as puzzles, stereoscopes, and eyeglasses, designed to improve visual performance. U.S. Pat. Nos.6,730,065; 6,515,006; 6,420,407; and 6,291,498 describe the use ofphentolamine to, for example, optimize pupil size in a patient. However,the need exists for additional compositions and methods that provideimprovement in visual performance.

Despite this need, it is difficult to prepare stable, aqueousformulations of phentolamine salt forms without the use of a chelatingagent, such as, disodium ethylenediaminetetraacetic acid (EDTA). U.S.Pat. No. 7,229,630 describes test results of various aqueousformulations containing phentolamine mesylate and states, for example,that the presence of a metal chelator is believed to be necessary tomaintain stability of the formulation.

In view of the need for better formulations for administeringphentolamine or a pharmaceutically acceptable salt thereof to the eye ofa patient, research has been performed and the present patentapplication describes the surprising discovery of stable, aqueousophthalmic solutions free of a chelating agent. The aqueous ophthalmicsolutions free of a chelating agent can be used to administerphentolamine mesylate to the eye of a patient, and the aqueousophthalmic solutions have demonstrated good stability upon storage.

Accordingly, the present invention addresses the aforementioned need forimproved formulations that can be administered to the eye of a patientfor improving visual performance, and the invention provides otherrelated advantages.

SUMMARY

The invention provides aqueous ophthalmic solutions of phentolamine orpharmaceutically acceptable salts thereof, medical kits, and methods forusing such solutions to improve visual performance in a patient. One ofthe benefits of the aqueous ophthalmic solutions is they havesurprisingly been found to be stable to extended storage, even thoughthey do not have a chelating agent. Another benefit of the aqueousophthalmic solutions is that they are well-suited for administration tothe eye of a patient in the form of an eye drop. For example, theaqueous ophthalmic solutions avoid or minimize any burning or stingingsensation often associated with certain phentolamine mesylate solutionsdescribed in the literature. Various aspects and embodiments of theinvention are described in further detail below.

Accordingly, one aspect of the invention provides an aqueous ophthalmicsolution free of a chelating agent, comprising: (a) about 0.1% (w/v) toabout 4% (w/v) of phentolamine or a pharmaceutically acceptable saltthereof; (b) about 1% (w/v) to about 6% (w/v) of at least one polyolcompound having a molecular weight less than 250 g/mol; (c) about 0.1 mMto about 10 mM of at least one buffer; and (d) water; wherein thesolution has a pH in the range of 4.0 to 7.5 and does not contain achelating agent.

Another aspect of the invention provides a method of improving visualperformance in a patient. The method comprises administering to the eyeof a patient in need thereof an effective amount of an aqueousophthalmic solution described herein to improve visual performance inthe patient. In certain embodiments, the improvement in visualperformance is improved visual acuity, such as an improvement in visualacuity under scotopic conditions, mesopic conditions, and/or photopicconditions.

Another aspect of the invention provides a method of reducing pupildiameter in a patient. The method comprises administering to the eye ofa patient in need thereof an effective amount of an aqueous ophthalmicsolution described herein to reduce pupil diameter in a patient. Incertain embodiments, the reduction in pupil diameter under mesopicconditions is at least 5% compared to the pupil diameter of the patientunder the same mesopic conditions but not having received said aqueousophthalmic solution.

Another aspect of the invention provides a method of reducing anaberrant focus of scattered light rays in a patient's eye. The methodcomprises administering to the eye of a patient in need thereof aneffective amount of an aqueous ophthalmic solution described herein toreduce aberrant focus of scattered light rays in the patient's eye.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a line graph of percent of initial concentration ofphentolamine mesylate remaining vs time for solutions stored at, forexample, 2-8° C., 25° C., and 40° C.

FIG. 1B is a line graph of area percent of phentolamine mesylate vs timefor solutions stored at, for example, 2-8° C., 25° C., and 40° C.

FIG. 1C is a line graph of pH of phentolamine mesylate solutions vs timefor solutions stored at, for example, 2-8° C., 25° C., and 40° C.

FIG. 2A is a line graph of percent of initial concentration ofphentolamine mesylate vs time for solutions containing 0.01% w/vphentolamine mesylate and solutions containing 2% w/v phentolaminemesylate stored at either 25° C. or 40° C.

FIG. 2B is a line graph of area percent of phentolamine mesylate vs timefor solutions containing 0.01% w/v phentolamine mesylate and solutionscontaining 2% w/v phentolamine mesylate stored at either 25° C. or 40°C.

FIG. 2C is a line graph of pH of the phentolamine mesylate solutions vstime for solutions containing 0.01% w/v phentolamine mesylate andsolutions containing 2% phentolamine mesylate stored at either 25° C. or40° C.

FIG. 3A is a line graph of percent of initial concentration ofphentolamine mesylate remaining vs time for solutions stored at 25° C.containing (i) phentolamine mesylate and mannitol (abbreviated P/M); (2)phentolamine mesylate, mannitol and acetate buffer without HPMC(abbreviated P/M/A); (3) phentolamine mesylate, mannitol and acetatebuffer with HPMC (abbreviated P/M/A/H); and (4) the Nova Formulation(identified as “Nova” in the figure legend).

FIG. 3B is a line graph of area percent of phentolamine mesylate vs timefor solutions stored at 25° C. containing (i) phentolamine mesylate andmannitol (abbreviated P/M); (2) phentolamine mesylate, mannitol andacetate buffer without HPMC (abbreviated P/M/A); (3) phentolaminemesylate, mannitol and acetate buffer with HPMC (abbreviated P/M/A/H);or (4) the Nova Formulation (identified as “Nova” in the figure legend).

FIG. 3C is a line graph of pH of the phentolamine mesylate solution vstime for solutions stored at 25° C. and containing (1) phentolaminemesylate and mannitol (abbreviated P/M); (2) phentolamine mesylate,mannitol and acetate buffer without HPMC (abbreviated P/M/A); (3)phentolamine mesylate, mannitol and acetate buffer with HPMC(abbreviated P/M/A/H); or (4) the Nova Formulation (identified as “Nova”in the figure legend).

FIG. 3D is a line graph of percent of initial concentration ofphentolamine mesylate remaining vs time for solutions stored at 40° C.containing (1) phentolamine mesylate and mannitol (abbreviated P/M); (2)phentolamine mesylate, mannitol and acetate buffer without HPMC(abbreviated P/M/A); (3) phentolamine mesylate, mannitol and acetatebuffer with HPMC (abbreviated P/M/A/H); or (4) the Nova Formulation(identified as “Nova” in the figure legend).

FIG. 3E is a line graph of area percent of phentolamine mesylate vs timefor solutions stored at 40° C. containing (1) phentolamine mesylate andmannitol (abbreviated P/M); (2) phentolamine mesylate, mannitol andacetate buffer without HPMC (abbreviated P/M/A); (3) phentolaminemesylate, mannitol and acetate buffer with HPMC (abbreviated P/M/A/H);or (4) the Nova Formulation (identified as “Nova” in the figure legend).

FIG. 3F is a line graph of pH of the phentolamine mesylate solution vstime for solutions stored at 40° C. containing (1) phentolamine mesylateand mannitol (abbreviated P/M); (2) phentolamine mesylate, mannitol andacetate buffer without HPMC (abbreviated P/M/A); (3) phentolaminemesylate, mannitol and acetate buffer with HPMC (abbreviated P/M/A/H);or (4) the Nova Formulation (identified as “Nova” in the figure legend).

FIG. 3G is a line graph of percent of initial concentration ofphentolamine mesylate remaining vs time for solutions stored at 2-8° C.containing (1) phentolamine mesylate and mannitol (abbreviated P/M); (2)phentolamine mesylate, mannitol and acetate buffer without HPMC(abbreviated P/M/A); (3) phentolamine mesylate, mannitol and acetatebuffer with HPMC (abbreviated P/M/A/H); or (4) the Nova Formulation(identified as “Nova” in the figure legend).

FIG. 3H is a line graph of area percent of phentolamine mesylate vs timefor solutions stored at 2-8° C. containing (1) phentolamine mesylate andmannitol (abbreviated P/M); (2) phentolamine mesylate, mannitol andacetate buffer without HPMC (abbreviated P/M/A); (3) phentolaminemesylate, mannitol and acetate buffer with HPMC (abbreviated P/M/A/H);or (4) the Nova Formulation (identified as “Nova” in the figure legend).

FIG. 3I is a line graph of pH of the phentolamine mesylate solution vstime for solutions stored at 2-8° C. containing (1) phentolaminemesylate and mannitol (abbreviated P/M); (2) phentolamine mesylate,mannitol and acetate buffer without HPMC (abbreviated P/M/A); (3)phentolamine mesylate, mannitol and acetate buffer with HPMC(abbreviated P/M/A/H); or (4) the Nova Formulation (identified as “Nova”in the figure legend).

DETAILED DESCRIPTION OF THE INVENTION

The invention provides aqueous ophthalmic solutions of phentolamine orpharmaceutically acceptable salts thereof, medical kits, and methods forusing such solutions to improve visual performance in a patient. Theaqueous ophthalmic solutions have surprisingly been found to be stableto extended storage, even though they do not have a chelating agent. Theaqueous ophthalmic solutions described herein offer the additionalbenefit that they are well-suited for administration to the eye of apatient in the form of an eye drop. For example, the aqueous ophthalmicsolutions avoid or minimize any burning or stinging sensation oftenassociated with certain phentolamine mesylate solutions described in theliterature. The practice of the present invention employs, unlessotherwise indicated, conventional techniques of organic chemistry andpharmacology. Various aspects of the invention are set forth below insections; however, aspects of the invention described in one particularsection are not to be limited to any particular section.

I. DEFINITIONS

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl,C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “Dextran 70” is art-recognized and refers to dextran having aweight average molecular weight of about 70,000 g/mol.

The abbreviation “q.s.” is art-recognized and refers to “quantitysufficient,” meaning the amount of material necessary to bring thesolution to the total volume.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers by wellknown methods, such as chiral-phase gas chromatography, chiral-phasehigh performance liquid chromatography, crystallizing the compound as achiral salt complex, or crystallizing the compound in a chiral solvent.Stereoisomers can also be obtained from stereomerically-pureintermediates, reagents, and catalysts by well-known asymmetricsynthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The present invention encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards.

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances.

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods of the present invention. Such organisms arepreferably mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of acompound or aqueous ophthalmic solution sufficient to effect beneficialor desired results. An effective amount can be administered in one ormore administrations, applications or dosages and is not intended to belimited to a particular formulation or administration route. As usedherein, the term “treating” includes any effect, e.g., lessening,reducing, modulating, ameliorating or eliminating, that results in theimprovement of the condition, disease, disorder, and the like, orameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see Martin inRemington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate (i.e., mesylate), 2-naphthalenesulfonate, nicotinate,oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, tosylate,undecanoate, and the like. Other examples of salts include anions of thecompounds of the present invention compounded with a suitable cationsuch as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C₁₋₄ alkyl group), and thelike.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The term “about” refers to, for example, 10% of the stated value. Forexample, about 10 mg of material refers to 9-11 mg of material.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

II. AQUEOUS OPHTHALMIC SOLUTIONS OF PHENTOLAMINE AND PHARMACEUTICALLYACCEPTABLE SALTS THEREOF

One aspect of the invention provides aqueous ophthalmic solutions freeof a chelating agent. The aqueous ophthalmic solutions comprise (a)phentolamine or a pharmaceutically acceptable salt thereof; (b) at leastone polyol compound, such as a polyol compound having a molecular weightless than 250 g/mol; (c) at least one buffer; and (d) water; wherein thesolution does not contain a chelating agent. One of the benefits of theaqueous ophthalmic solutions is they have surprisingly been found to bestable to extended storage, even though they do not have a chelatingagent. In addition, another benefit of the aqueous ophthalmic solutionsis they avoid or minimize any burning or stinging sensation oftenassociated with certain phentolamine mesylate solutions described in theliterature. The amount of ingredients in the aqueous ophthalmicsolutions may be selected in order to achieve particular performanceproperties, such as stability to storage, minimize irritation to the eyeof a patient, and enhance penetration of phentolamine into the eye of apatient.

One exemplary preferred solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.1% (w/v) to about 4% (w/v)of phentolamine or a pharmaceutically acceptable salt thereof; (b) about1% (w/v) to about 6% (w/v) of at least one polyol compound having amolecular weight less than 250 g/mol; (c) about 0.1 mM to about 10 mM ofat least one buffer; and (d) water; wherein the solution has a pH in therange of 4.0 to 7.5 and does not contain a chelating agent.

Exemplary components and features of the aqueous ophthalmic solution aredescribed in more detail below.

Phentolamine & Pharmaceutically Acceptable Salts

The aqueous ophthalmic solution comprises phentolamine or apharmaceutically acceptable salt of phentolamine. Exemplarypharmaceutically acceptable salts include, for example, the hydrochloricacid salt and mesylate salt. Accordingly, in certain embodiments, thesolution comprises phentolamine (i.e., as the free base). In certainother embodiments, the solution comprises phentolamine hydrochloride. Incertain yet other embodiments, the solution comprises phentolaminemesylate.

The amount of phentolamine or a pharmaceutically acceptable salt thereofin the aqueous ophthalmic solution may be adjusted in order to achievedesired performance properties. For example, where is it desired toprovide a larger amount of phentolamine (or pharmaceutically acceptablesalt thereof) to the patient in a single administration of the aqueousophthalmic solution, the concentration of phentolamine (orpharmaceutically acceptable salt thereof) is increased in the aqueousophthalmic solution. Single administration of aqueous ophthalmicsolutions having a higher concentration of phentolamine (orpharmaceutically acceptable salt thereof) may provide the patient withimproved visual performance for a longer duration of time because morephentolamine (or pharmaceutically acceptable salt thereof) isadministered to the patient.

Accordingly, in certain embodiments, the aqueous ophthalmic solutioncomprises from about 0.1% (w/v) to about 2% (w/v) of phentolamine or apharmaceutically acceptable salt thereof. In certain embodiments, theaqueous ophthalmic solution comprises from about 0.25% (w/v) to about 2%(w/v) of phentolamine or a pharmaceutically acceptable salt thereof. Incertain other embodiments, the aqueous ophthalmic solution comprisesfrom about 0.5% (w/v) to about 2% (w/v) of phentolamine or apharmaceutically acceptable salt thereof. In certain other embodiments,the aqueous ophthalmic solution comprises from about 0.25% (w/v) toabout 1% (w/v) of phentolamine or a pharmaceutically acceptable saltthereof. In certain other embodiments, the aqueous ophthalmic solutioncomprises about 1% (w/v) of phentolamine or a pharmaceuticallyacceptable salt thereof. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.1% (w/v) to about 4% (w/v) ofphentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.1% (w/v) to about 2% (w/v) ofphentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.5% (w/v) to about 2% (w/v) ofphentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.25% (w/v) to about 1% (w/v)of phentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises about 1% (w/v) of phentolamine mesylate.In certain other embodiments, the aqueous ophthalmic solution comprisesabout 0.25% (w/v) or about 0.5% (w/v) of phentolamine mesylate.

Polyol Compounds

The aqueous ophthalmic solution comprises one or more polyol compounds.The polyol compound is an organic compound having at least two hydroxylgroups (e.g., from 2 to about 6 hydroxyl groups). The polyol compound isbeneficial to the aqueous ophthalmic solution because, for example, itcan increase the stability of the aqueous ophthalmic solution to storageand/or modify the tonicity of the aqueous ophthalmic solution. Exemplarypolyol compounds include, for example, mannitol, glycerol, propyleneglycol, ethylene glycol, sorbitol, and xylitol.

The aqueous ophthalmic solution may contain a single polyol compound ora mixture of one or more polyol compounds. In other words, the aqueousophthalmic solution comprises at least one polyol compound. In certainembodiments, the aqueous ophthalmic solution comprises at least onepolyol compound that is mannitol, glycerol, propylene glycol, ethyleneglycol, sorbitol, or xylitol. In certain other embodiments, the at leastone polyol compound is mannitol. In certain other embodiments, the atleast one polyol compound is glycerol. In certain other embodiments, theat least one polyol compound is propylene glycol. In certain otherembodiments, the at least one polyol compound is mannitol, and thesolution further comprises glycerol. In certain other embodiments, theat least one polyol compound is mannitol, and the solution furthercomprises propylene glycol. In certain other embodiments, the at leastone polyol compound is glycerol, and the solution further comprisespropylene glycol. In certain other embodiments, the mannitol describedin embodiments above is D-mannitol.

The amount of the at least one polyol compound in the aqueous ophthalmicsolution may be selected in order to achieve desired performanceproperties for the solution. The polyol compound may, for example,increase the stability of the solution to storage and/or modify thetonicity of the solution to make it more suitable for administration tothe eye of a patient. In certain embodiments, the aqueous ophthalmicsolution comprises from about 2% (w/v) to about 5% (w/v) of the at leastone polyol compound. In certain other embodiments, the aqueousophthalmic solution comprises from about 3.5% (w/v) to about 4.5% (w/v)of the at least one polyol compound. In certain other embodiments, theaqueous ophthalmic solution comprises about 4% (w/v) of the at least onepolyol compound. In certain other embodiments, the aqueous ophthalmicsolution comprises from about 2% (w/v) to about 3% (w/v) mannitol, andabout 0.5% (w/v) to about 1.5% (w/v) glycerin. In certain otherembodiments, the mannitol described in embodiments above is D-mannitol.

In certain embodiments, the amount of polyol may be selected based onthe amount of phentolamine (or pharmaceutically acceptable saltthereof), such that there is an inverse relationship between the amountof phentolamine (or pharmaceutically acceptable salt thereof) and thepolyol in order to achieve isotonicity with the eye. For example, inembodiments where the aqueous ophthalmic solution contains about 2%(w/v) phentolamine, mannitol is present in the solution at aconcentration of about 3% (w/v). In embodiments where the aqueousophthalmic solution contains about 1% (w/v) phentolamine, mannitol ispresent in the solution at a concentration of about 4% (w/v). To furtherillustrate this principle, in embodiments where the aqueous ophthalmicsolution contains about 0.5% (w/v) phentolamine, mannitol may be presentin the solution at a concentration of about 4.5% (w/v). In certainembodiments, the mannitol described in embodiments above is D-mannitol.

It is appreciated that the aqueous ophthalmic solution can containadditional ingredients described herein, such as various polymermaterials. One such embodiment is an aqueous ophthalmic solutioncomprising, for example, at least one polyol compound that is propyleneglycol, and further comprising polypropylene glycol, such aspolypropylene glycol having a weight average molecular weight in therange of about 5,000 g/mol to about 100,000 g/mol.

Poly(C₂₋₄alkylene)glycol Polymer

The aqueous ophthalmic solution may optionally comprise apoly(C₂₋₄alkylene)glycol polymer. An exemplary poly(C₂₋₄alkylene)glycolpolymer is polypropylene glycol, such as a polypropylene glycol having aweight average molecular weight in the range of about 5,000 g/mol toabout 100,000 g/mol, about 10,000 g/mol to about 50,000 g/mol, or about50,000 g/mol to about 100,000 g/mol.

Dextran

The aqueous ophthalmic solution may optionally comprise dextran. Dextranis a commercially available, branched polysaccharide comprising glucosemolecules. The amount of dextran in the aqueous ophthalmic solution maybe selected to achieve certain performance properties. In certainembodiments, the aqueous ophthalmic solution comprises from about 0.01%(w/v) to about 2% (w/v) dextran. In certain other embodiments, theaqueous ophthalmic solution comprises from about 0.01% (w/v) to about 1%(w/v) dextran.

The dextran may be further characterized according to its weight averagemolecular weight. In certain embodiments, the dextran has a weightaverage molecular weight in the range of about 65,000 g/mol to about75,000 g/mol. In certain other embodiments, the dextran has a weightaverage molecular weight of about 70,000 g/mol. In yet otherembodiments, the dextran has a weight average molecular weight in therange of about 5,000 g/mol to about 100,000 g/mol, about 10,000 g/mol toabout 50,000 g/mol, or about 50,000 g/mol to about 100,000 g/mol.

Cellulose Agent

The aqueous ophthalmic solution may optionally comprise a celluloseagent. Exemplary cellulose agents include, for example, cellulose,carboxymethyl cellulose, hydroxyethylcellulose, hydroxpropylcellulose,and hydroxypropylmethyl cellulose. In certain embodiments, the celluloseagent is hydroxypropylmethyl cellulose. In certain other embodiments,the cellulose agent is cellulose, carboxymethyl cellulose,hydroxyethylcellulose, or hydroxpropylcellulose. The amount of celluloseagent in the aqueous ophthalmic solution may be selected in order toachieve desired performance properties. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.01%(w/v) to about 2% (w/v) cellulose agent.

The cellulose agent may be further characterized according to its weightaverage molecular weight. In certain embodiments, the cellulose agenthas a weight average molecular weight in the range of about 5,000 g/molto about 100,000 g/mol, about 10,000 g/mol to about 50,000 g/mol, orabout 50,000 g/mol to about 100,000 g/mol.

Buffer

The aqueous ophthalmic solution comprises at least one buffer. Thebuffer imparts to the solution a buffering capacity, that is, thecapacity to neutralize, within limits, either acids or bases (alkali)with relatively little or no change in the original pH. The buffer maybe an acid, a base, or a combination of an acid and a base. The buffermay be organic, inorganic, or a combination of organic and inorganiccomponents. It should be understood that the buffer at least partiallydissociates in aqueous solution to form a mixture of, e.g., an acid andconjugate base or a base and conjugate acid. For example, the buffer maybe a combination of a carboxylic acid and its carboxylate salt. Inanother embodiment, the buffer may be a combination of an acid and abase, where the acid and the base are not conjugates. For example, theacid may be boric acid and the base may betris(hydroxymethyl)aminomethane (TRIS).

Exemplary buffers include organic acids (e.g., acetic acid, sorbic acid,and oxalic acid), a borate salt, a hydrogen carbonate salt, a carbonatesalt, a gluconate salt, a lactate salt, a phosphate salt, a propionatesalt, a perborate salt, tris-(hydroxymethyl)amineomethane (TRIS),bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)aminoalcohol (bis-tris),N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricene),N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine,3-(N-morpholino)propanesulfonic acid, N-(carbamoylmethyl)taurine (ACES),an amino acid, salts thereof, and combinations thereof. It should beunderstood that the salt form of a buffer may comprise any suitablecounterion. For example, the salt form of an acid may comprise an alkalior alkaline earth metal counterion.

The buffer can be characterized according to its strength, i.e., thebuffering capacity. The buffering capacity can be tested, for example,by determining the millimoles (mM) of strong acid or base (orrespectively, hydrogen or hydroxide ions) required to change the pH of abuffer solution by one unit when added to one liter (a standard unit) ofthe buffer solution. The buffering capacity generally depends on thetype and concentration of the buffer components and can be greater inparticular pH ranges. For example, a buffer may have an optimalbuffering capacity in a pH range near the pK_(a) of the buffer, e.g.,within about 1 pH unit or within about 2 pH units of the pK_(a) thebuffer. In certain embodiments, the buffer is a weak buffer, such as analkali metal carboxylate (e.g., sodium acetate).

In certain embodiments, the buffer is a weak acid buffer having one ormore of the following characteristics: (a) a pKa of between about 4.0and about 6.0; more preferably, between about 4.5 and about 5.5; and (b)a lipophilicity value Log P of from about −0.50 to about 1.5; morepreferably, from about −0.25 to about 1.35.

The amount of buffer can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. For example,in certain embodiments, the buffer may be present at a concentration ofless than about 10 mM, less than about 7 mM, less than about 5 mM, lessthan about 3 mM, or less than about 2 mM. In some embodiments, thebuffer may be present at a concentration of from about 1 mM to about 10mM, from about 1 mM to about 7 mM, from about 1 mM to about 5 mM, fromabout 1 mM to about 3 mM, from about 1 mM to about 2 mM, from about 2 mMto about 5 mM, or from about 2 mM to about 3 mM. In yet otherembodiments, the buffer is present at a concentration of about 3 mM.

The amount and identity of the buffer may be selected in order toachieve certain performance properties for the aqueous ophthalmicsolution. For example, the amount of buffer may impact the quantity ofacid that may be neutralized before there is substantial change in thepH of the aqueous ophthalmic solution. Also, the amount of buffer mayimpact the tonicity of the aqueous ophthalmic solution. Desirably, thequantity and identity of the buffer should be selected in order tominimize any irritation that may be caused by administration of theaqueous ophthalmic solution to the eye of a patient. Accordingly, incertain embodiments, the buffer is present at a concentration in therange of about 2 mM to about 4 mM. In yet other embodiments, the bufferis present at a concentration of about 3 mM. In certain embodiments, thebuffer comprises an alkali metal alkylcarboxylate. In certain otherembodiments, the buffer comprises an alkali metal acetate. In yet otherembodiments, the buffer comprises sodium acetate.

Solution pH

The aqueous ophthalmic solution may be characterized according to the pHof the solution. Desirably, the aqueous ophthalmic solution has a pH inthe range of 4.0 to 7.5. In certain embodiments, the aqueous ophthalmicsolution has a pH in the range of 4.5 to 7.5. In certain embodiments,the solution has a pH in the range of 4.5 to 6.0. In certain otherembodiments, the solution has a pH in the range of 4.5 to 5.5. In yetother embodiments, the solution has a pH in the range of 4.7 to 5.1.

Additional Materials for Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions may contain additional materials inorder to make the composition more suitable for administration to theeye of a patient. Exemplary additional materials are described below andinclude, for example, a tonicity modifier, preservative, antioxidant,viscosity modifying agent, stabilizing agent, corneal permeationenhancing agent, and surfactants.

A. Tonicity Modifier

The aqueous ophthalmic solution may optionally comprise one or moretonicity modifiers. The tonicity modifier may be ionic or non-ionic. Incertain embodiments, the tonicity modifier may be a salt, acarbohydrate, or a polyol. Exemplary tonicity modifiers include alkalimetal or alkaline earth metal halides (such as LiBr, LiCl, LiI, KBr,KCl, KI, NaBr, NaCl, NaI, CaCl₂, and MgCl₂), boric acid, dextran (e.g.,Dextran 70), cyclodextrin, dextrose, mannitol, glycerin, urea, sorbitol,propylene glycol, or a combination thereof.

It is appreciated that the tonicity modifier may be added to the aqueousophthalmic solution in an amount sufficient to provide a desiredosmolality. In certain embodiments, the tonicity modifier is present inthe aqueous ophthalmic solution in an amount sufficient so that theaqueous ophthalmic solution has an osmolality ranging from about 50 toabout 1000 mOsm/kg, from about 100 to about 400 mOsm/kg, from about 200to about 400 mOsm/kg, or from about 280 to about 380 mOsm/kg. In certainembodiments, a tonicity modifier may be present in an amount rangingfrom about 0.01% (w/v) to about 7% (w/v), about 0.01% (w/v) to about 5%(w/v), about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1%(w/v), about 0.05% (w/v) to about 5% (w/v), about 0.05% (w/v) to about0.5% (w/v), about 1% (w/v) to about 3% (w/v), or about 2% (w/v) to about4% (w/v), of the aqueous ophthalmic solution.

B. Preservative

The aqueous ophthalmic solution may optionally comprise one or morepreservatives in order to, for example, reduce or prevent microbialcontamination. Exemplary preservatives include quaternary ammonium saltssuch as polyquaternium-1, cetrimide, benzalkonium chloride, orbenzoxonium chloride; alkyl-mercury salts of thiosalicylic acid such asthiomersal, phenylmercuric nitrate, phenylmercuric acetate, orphenylmercuric borate; parabens such as methylparaben or propylparaben;alcohols such as chlorobutanol, benzyl alcohol, phenyl ethanol,cyclohexanol, 3-pentanol, or resorcinol; a peroxide; chlorine dioxide orPURITE; guanidine derivatives such as chlorohexidine gluconate orpolyaminopropyl biguanide; and combinations thereof.

The amount of preservative can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the preservative is present in an amount less than about 5%(w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the preservative is present inan amount ranging from about 0.01% (w/v) to about 5% (w/v), about 0.01%(w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05%(w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), ofthe aqueous ophthalmic solution.

C. Antioxidant

The aqueous ophthalmic solution may optionally comprise one or moreantioxidants. Exemplary antioxidants for use in the aqueous ophthalmicsolutions described herein include water soluble antioxidants such asascorbic acid, cysteine hydrochloride, sodium bisulfate, sodiummetabisulfite, sodium bisulfite, sodium sulfite, and the like; andoil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like.

The amount of antioxidant can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the antioxidant is present in an amount less than about 5%(w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the antioxidant is present in anamount ranging from about 0.01% (w/v) to about 5% (w/v), about 0.01%(w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05%(w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), ofthe aqueous ophthalmic solution.

D. Viscosity Modifying Agent

The aqueous ophthalmic solution may optionally comprise one or moreviscosity modifying agents. The viscosity modifying agent may be used,for example, to increase the absorption of an active agent or increasethe retention time of the aqueous ophthalmic solution in the eye.Exemplary viscosity modifying agents include polyvinylpyrrolidone,methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose,hydroxpropylcellulose, carboxymethylcellulose (CMC) and salts thereof(e.g., CMC sodium salt), gelatin, cellulose glycolate, sorbitol,niacinamide, an alpha-cyclodextran, polyvinyl alcohol, polyethyleneglycol, hyaluronic acid, a polysachcharaide, a monosaccharide, andcombinations thereof.

The amount of viscosity modifying agent can be adjusted in order toachieve desired performance properties for the aqueous ophthalmicsolution. In certain embodiments, the viscosity modifying agent ispresent in an amount less than about 10% (w/v), 5% (w/v), 3% (w/v), 1%(w/v), or 0.1% (w/v) of the aqueous ophthalmic solution. In certainother embodiments, the viscosity modifying agent is present in an amountranging from about 0.01% (w/v) to about 5% (w/v), about 0.01% (w/v) toabout 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05% (w/v) toabout 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), of the aqueousophthalmic solution. In certain other embodiments, the viscositymodifying agent is present in an amount sufficient to provide an aqueousophthalmic solution with a viscosity in the range of about 30 centipoiseto about 100 centipoise.

E. Corneal Permeation Enhancing Agent

The aqueous ophthalmic solution may optionally comprise one or moreagents for enhancing corneal permeation of phentolamine (or apharmaceutically acceptable salt thereof). Exemplary agents forenhancing corneal permeation include polymers, organic acids, esters ofan organic acid (e.g., a monoglyceride of fatty acid having 8 to 12carbon atoms), cyclodextrin, benzalkonium chloride (BAK), EDTA, caprylicacid, citric acid, boric acid, sorbic acid, polyoxyethylene-20-stearylether (PSE), polyethoxylated castor oil (PCO), deoxycholic acid sodiumsalt (DC), cetylpyridinium chloride (CPC), laurocapram,hexamethylenelauramide, hexamethyleneoctanamide, decylmethylsulfoxide,methyl sulfone, dimethyl sulfoxide, and combinations thereof.

The amount of corneal permeation enhancing agent can be adjusted inorder to achieve desired performance properties for the aqueousophthalmic solution. In certain embodiments, the corneal permeationenhancing agent is present in an amount less than about 10% (w/v), 5%(w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmic solution. Incertain other embodiments, the corneal permeation enhancing agent ispresent in an amount ranging from about 0.01% (w/v) to about 5% (w/v),about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v),about 0.05% (w/v) to about 5% (w/v), about 0.05% (w/v) to about 0.5%(w/v), about 1% (w/v) to about 3% (w/v), or about 2% (w/v) to about 4%(w/v), of the aqueous ophthalmic solution.

F. Solubilizing Agent

The aqueous ophthalmic solution may optionally comprise one or moresolubilizing agents to improve the solubility of phentolamine (or apharmaceutically acceptable salt thereof) in the aqueous ophthalmicsolution. Exemplary solubilizing agents include, for example, a fattyacid glycerol poly-lower alkylene (i.e., a C₁ to C₇, linear or branched)glycol ester, fatty acid poly-lower alkylene glycol ester, polyalkyleneglycol (e.g., polyethylene glycol), glycerol ether of vitamin E,tocopherol polyethylene glycol 1000 succinate (TPGS), tyloxapol,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84and P-103), cyclodextrin, and combinations thereof.

The amount of solubilizing agent can be adjusted in order to achievedesired performance properties for the aqueous ophthalmic solution. Incertain embodiments, the solubilizing agent is present in an amount lessthan about 10% (w/v), 5% (w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of theaqueous ophthalmic solution. In certain other embodiments, thesolubilizing agent is present in an amount ranging from about 0.01%(w/v) to about 5% (w/v), about 0.01% (w/v) to about 1% (w/v), about 0.1%(w/v) to about 1% (w/v), about 0.05% (w/v) to about 5% (w/v), or about0.05% (w/v) to about 0.5% (w/v), of the aqueous ophthalmic solution.

G. Stabilizing Agent

The aqueous ophthalmic solution may optionally comprise one or morestabilizing agents in order to improve the stability of the aqueousophthalmic solution to storage, etc. Stabilizing agents described in thepharmaceutical literature are contemplated to be amenable for use in theaqueous ophthalmic solutions described herein. Exemplary stabilizingagents include an alcohol (e.g., polyols, such as mannitol, glycerol,propylene glycol, sorbitol, and xylitol), polyalkylene glycols such aspolyethylene glycol, polypropylene glycol, polyethylene glycol-nonphenolether, polyethylene glycol sorbitan monolaurate, polyethylene glycolsorbitan monooleate, polyethylene glycol sorbitan monooleate,polyethylene glycol sterarate, polyethylene glycol polypropylene glycolether, polyvinyl alcohol, polyvinyl pyrrolidine, ascorbic acid, vitaminE, N-acetylcarnosine (NAC), sorbic acid, and combinations thereof. Incertain embodiments, the stabilizing agent is a polymer, such as one ofthe polymers mentioned above.

The amount of stabilizing agent can be adjusted in order to achievedesired performance properties for the aqueous ophthalmic solution. Incertain embodiments, the stabilizing agent is present in an amount lessthan about 10% (w/v), 5% (w/v), or 1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the stabilizing agent is presentin an amount ranging from about 0.01% (w/v) to about 5% (w/v), about0.01% (w/v) to about 1% (w/v), or about 0.01% (w/v) to about 0.1% (w/v)of the aqueous ophthalmic solution.

H. Surfactant

The aqueous ophthalmic solution may optionally comprise one or moresurfactants. Exemplary surfactants include Polysorbate 20 (i.e.,polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (i.e.,polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (i.e.,polyoxyethylene (20) sorbitan monostearate), Polysorbate 80 (i.e.,polyoxyethylene (20) sorbitan monooleate), glyceryl stearate, isopropylstearate, polyoxyl stearate, propylene glycol stearate, sucrosestearate, polyethylene glycol, a polypropylene oxide, a polypropyleneoxide copolymer, Pluronic F68, Pluronic F-84, Pluronic P-103, an alcoholethoxylate, an alkylphenol ethoxylate, an alkyl glycoside, an alkylpolyglycoside, a fatty alcohol, hydroxypropylmethyl cellulose (HPMC),carboxymethyl cellulose (CMC), cyclodextrin, a polyacrylic acid,phosphatidyl chloline, phosphatidyl serine, and combinations thereof.

The amount of surfactant can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the surfactant is present in an amount less than about 10%(w/v), 5% (w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueousophthalmic solution. In certain other embodiments, the surfactant ispresent in an amount ranging from about 0.01% (w/v) to about 5% (w/v),about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v),about 0.05% (w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5%(w/v), of the aqueous ophthalmic solution.

I. Demulcent Polymers

The aqueous ophthalmic solution may optionally comprise one or moredemulcent polymers. Because of their ability to hold large amounts ofwater, demulcent polymers are useful for coating and moisturizing thecornea of the eye. Exemplary demulcent polymers include cellulosederivatives, dextran 40, dextran 70, gelatin, and liquid polyols.

J. Wetting Agents

The aqueous ophthalmic solution may optionally comprise one or morewetting agents. Wetting agents can be used to wet the surface of theeye. Exemplary wetting agents include polysorbates, poloxamers,tyloxapol, and lecithin.

K. Additional Materials

The aqueous ophthalmic solutions may optionally comprise one or moreadditional materials, such as acetylcysteine, cysteine, sodium hydrogensulfite, butyl-hydroxyanisole, butyl-hydroxytoluene, alpha-tocopherolacetate, thiourea, thiosorbitol, sodium dioctyl sulfosuccinate,monothioglycerol, lauric acid sorbitol ester, triethanol amine oleate,or palmitic acid esters.

Further, the aqueous ophthalmic solutions may comprise a carrier, suchas one or more of the exemplary carriers are described in for example,Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co.,Easton, Pa. [1975]). The carrier can be, for example, a mixture of waterand a water-miscible solvent (e.g., an alcohol such as glycerin, avegetable oil, or a mineral oil). Other exemplary carriers include amixture of water and one or more of the following materials:hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, analkali metal salt of carboxymethylcellulose, hydroxymethylcellulose,methylhydroxypropylcellulose, hydroxypropylcellulose, ethyl oleate,polyvinylpyrrolidone, an acrylate polymer, a methacrylate polymer, apolyacrylamide, gelatin, an alginate, a pectin, tragacanth, karaya gum,xanthan gum, carrageenin, agar, acacia, a starch (such as starch acetateor hydroxypropyl starch), polyvinyl alcohol, polyvinyl methyl ether,polyethylene oxide, or a cross-linked polyacrylic acid.

Exemplary Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions having been generally described abovewill now be more specifically described by reference to the followingmore specific examples. The following more specific examples are onlyexemplary and are not intended to limit the scope of the invention inany way.

One such exemplary solution is an aqueous ophthalmic solution free of achelating agent comprising: (a) about 0.1% (w/v) to about 2% (w/v) ofphentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of at leastone polyol compound selected from the group consisting of is mannitol,glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of analkali metal acetate; and (d) water; wherein the solution has a pH inthe range of 4 to 6 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate. In certainembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.25% (w/v) to about 1% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4 to 6.

Another such exemplary solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.5% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water; wherein the solution has a pHin the range of 4.5 to 5.5 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.5% (w/v) to about 2% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4.5 to 5.5.

Another such exemplary solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water; wherein the solution has a pHin the range of 4.5 to 5.5 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate. In certain otherembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.5% (w/v) to about 1% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4.5 to 5.5.

Further exemplary aqueous ophthalmic solutions are provided in Tables1-3 below, where in each instance the solution has a pH in the range of4.7 to 5.1.

TABLE 1 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component A1 B1 C1 D1 E1 F1 G1 H1 Phentolamine 1.5 1 0.5 1 1 1 1 1mesylate (% w/v) Mannitol 4 4 4 3 3 2 2 4 (% w/v) Sodium 3 3 3 3 3 3 3 3acetate (mM) Glycerol 0 0 0 0.5 0 1 0 0 (% w/v) Propylene 0 0 0 0 0.5 01 0 glycol (% w/v) Dextran 0 0 0 0 0 0 0 0.1 70 (% w/v) Water q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s.

TABLE 2 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component A2 B2 C2 D2 E2 F2 Phentolamine mesylate 0.25 0.25 0.25 0.250.25 0.25 (% w/v) Mannitol (% w/v) 4 3 3 2 2 4 Sodium acetate (mM) 3 3 33 3 3 Glycerol (% w/v) 0 0.5 0 1 0 0 Propylene glycol 0 0 0.5 0 1 0 (%w/v) Dextran 70 (% w/v) 0 0 0 0 0 0.1 Water q.s. q.s. q.s. q.s. q.s.q.s.

TABLE 3 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component A3 B3 C3 D3 E3 F3 G3 H3 Phentolamine 1.5 1 0.5 0.25 1 1 1 1mesylate (% w/v) Mannitol 4 4 4 4 3 2 2 4 (% w/v) Sodium 3 3 3 3 3 3 2 3acetate (mM) Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

Another exemplary aqueous ophthalmic solution comprises phentolaminemesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v), dextran having aweight average molecular weight of about 70,000 g/mol (e.g., at 0.1%w/v), hydroxypropyl methylcellulose (e.g., at 0.3% w/v), potassiumchloride, purified water, sodium borate, and sodium chloride; whereinthe solution has a pH in the range of about 4 to about 6. In certainembodiments, the solution has a pH in the range of 4.5 to 5.1. Incertain embodiments, the aqueous ophthalmic solution consistsessentially of phentolamine mesylate (e.g., at 1% w/v), mannitol (e.g.,at 4% w/v), dextran having a weight average molecular weight of about70,000 g/mol (e.g., at 0.1% w/v), hydroxypropyl methylcellulose (e.g.,at 0.3% w/v), potassium chloride, purified water, sodium borate, andsodium chloride; wherein the solution has a pH in the range of 4 to 6.In certain other embodiments, the aqueous ophthalmic solution consistsof phentolamine mesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v),dextran having a weight average molecular weight of about 70,000 g/mol(e.g., at 0.1% w/v), hydroxypropyl methylcellulose (e.g., at 0.3% w/v),potassium chloride, purified water, sodium borate, and sodium chloride;wherein the solution has a pH in the range of 4.5 to 5.1.

Another exemplary aqueous ophthalmic solution comprises phentolaminemesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v), sodium acetate(e.g., at 3 mM), and water, wherein the solution has a pH in the rangeof about 4 to about 6. In certain embodiments, the solution has a pH inthe range of 4.5 to 5.1. In certain embodiments, the aqueous ophthalmicsolution consists essentially of phentolamine mesylate (e.g., at 1%w/v), mannitol (e.g., at 4% w/v), sodium acetate (e.g., at 3 mM), andwater, wherein the solution has a pH in the range of 4 to 6. In certainembodiments, the aqueous ophthalmic solution comprises phentolaminemesylate at 1% w/v, mannitol 4% w/v, sodium acetate at 3 mM, and water,wherein the solution has a pH in the range of 4.5 to 5.1. In certainother embodiments, the aqueous ophthalmic solution consists ofphentolamine mesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v),sodium acetate (e.g., at 3 mM), and water, wherein the solution has a pHin the range of 4.5 to 5.1. In certain embodiments, the aqueousophthalmic solution consists essentially of phentolamine mesylate at 1%w/v, mannitol 4% w/v, sodium acetate at 3 mM, and water, wherein thesolution has a pH in the range of 4.5 to 5.1.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.1% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water; wherein the solution has a pHin the range of 4 to 6 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.25% (w/v) to about 2%(w/v) of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.1% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent. In certain embodiments, the aqueousophthalmic solution free of a chelating agent that comprises about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.5 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 1% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 1 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.1% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent. In certainembodiments, the aqueous ophthalmic solution free of a chelating agentthat comprises about 0.25% (w/v) to about 1% (w/v) of phentolaminemesylate.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.5% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent.

Stability Features of Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions described herein may be furthercharacterized according to their stability features, such as thepercentage of phentolamine (or pharmaceutically acceptable salt thereof)that is present in the aqueous ophthalmic solution after storage for acertain length of time. As explained above, one of the benefits of thepresent aqueous ophthalmic solutions is that they possess good stabilityover extended periods of time, even though they do not have a chelatingagent.

Accordingly, in certain embodiments, the aqueous ophthalmic solution ischaracterized by less than 2% of the phentolamine or pharmaceuticallyacceptable salt thereof degrades upon storage of the solution at 25° C.for 12 weeks. In certain other embodiments, the aqueous ophthalmicsolution is characterized by less than 2% of the phentolamine orpharmaceutically acceptable salt thereof degrades upon storage at 25° C.for 24 weeks (or 36 weeks or 48 weeks). In certain other embodiments,the aqueous ophthalmic solution is characterized by less than 10% of thephentolamine or pharmaceutically acceptable salt thereof degrades uponstorage at 25° C. for 1 year or 2 years. In yet other embodiments, lessthan 7% of the phentolamine or pharmaceutically acceptable salt thereofdegrades upon storage at 40° C. for 12 weeks (or 24, 36, or 48 weeks).In yet other embodiments, the aqueous ophthalmic solution ischaracterized by less than 10% by weight of the phentolamine orpharmaceutically acceptable salt thereof degrades upon storage at 25° C.for 18 months, 24 months, or 36 months. In yet other embodiments, theaqueous ophthalmic solution is characterized by less than 10% by weightof the phentolamine or pharmaceutically acceptable salt thereof degradesupon storage at temperature in the range of 2-8° C. for 18 months, 24months, or 36 months. In yet other embodiments, the aqueous ophthalmicsolution is characterized by less than 4% by weight (or preferably lessthan 3% by weight) of the phentolamine or pharmaceutically acceptablesalt thereof degrades upon storage at 25° C. for 18 months, 24 months,or 36 months. In yet other embodiments, less than 10% by weight of thephentolamine or pharmaceutically acceptable salt thereof degrades uponstorage at 40° C. for 4, 5, or 6 months.

III. THERAPEUTIC APPLICATIONS

The invention provides methods of improving vision in a patient usingthe aqueous ophthalmic solutions described herein.

Methods of Improving Visual Performance

One aspect of the invention provides a method of improving visualperformance in a patient. The method comprises administering to the eyeof a patient in need thereof an effective amount of an aqueousophthalmic solutions described herein, such as an aqueous ophthalmicsolution described in Section II, to improve visual performance in thepatient.

Visual performance pertains to the patient's overall vision quality andincludes a patient's ability to see clearly, as well as ability todistinguish between an object and its background. One aspect of visualperformance is visual acuity. Visual acuity is a measure of a patient'sability to see clearly. Visual acuity can be measured using, forexample, a Snellen chart, and the visual acuity measurement can be takenunder conditions that test low-contrast visual acuity or underconditions that test high-contrast visual acuity. Further, the visualacuity measurement can be taken under scotopic conditions, mesopicconditions, and/or photopic conditions. Another aspect of visualperformance is contrast sensitivity. Contrast sensitivity is a measureof the patient's ability to distinguish between an object and itsbackground. Contrast sensitivity can be measured using, for example, aHolladay Automated Contrast Sensitivity System. The contrast sensitivitycan be measured under various light conditions, including, for example,photopic conditions, mesopic conditions, and scotopic conditions, eacheither with or without glare. In certain embodiments, the contrastsensitivity is measured under mesopic conditions either with or withoutglare.

In certain embodiments, the improvement in visual performance providedby the method is improved visual acuity. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under scotopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under mesopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under photopic conditions. In certain embodiments, theimprovement in visual acuity is a two-line improvement in the patient'svision as measured using the Snellen chart. In certain otherembodiments, the improvement in visual acuity is a one-line improvementin the patient's vision as measured using the Snellen chart.

In certain embodiments, the improvement in visual performance providedby the method is improved contrast sensitivity. The improvement incontrast sensitivity can be measured under various light conditions,such as photopic conditions, mesopic conditions, and scotopicconditions. In certain embodiments, the improvement in visualperformance provided by the method is improved contrast sensitivityunder photopic conditions. In certain embodiments, the improvement invisual performance provided by the method is improved contrastsensitivity under mesopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedcontrast sensitivity under scotopic conditions. Further, contrastsensitivity can be measured in the presence of glare or the absence ofglare. All combinations of light conditions and glare are contemplated.

Results achieved by the therapeutic methods can be characterizedaccording to the patient's improvement in contrast sensitivity. Forexample, in certain embodiments, the improvement in contrast sensitivityis a 10% (or 20%, 30%, 50%, 60%, or 70%) improvement measured undermesopic conditions using the Holladay Automated Contrast SensitivitySystem. In certain embodiments, the improvement in contrast sensitivityis a 10% (or 20%, 30%, 50%, 60%, or 70%) improvement measured underphotopic conditions using the Holladay Automated Contrast SensitivitySystem. In certain other embodiments, the improvement in contrastsensitivity is at least a 10% (or 20%, 30%, 50%, 60%, or 70%)improvement measured under mesopic conditions or scotopic conditionsusing the Holladay Automated Contrast Sensitivity System.

In certain other embodiments, the improvement in visual performanceprovided by the method is both (i) improved visual acuity (such as underscotopic conditions, mesopic conditions, and/or photopic conditions) and(ii) improved contrast sensitivity (such as under scotopic conditions,mesopic conditions, and/or photopic conditions).

Methods of Reducing Pupil Diameter

One aspect of the invention provides a method of reducing pupil diameterin a patient. The method comprises administering to the eye of a patientin need thereof an effective amount of an aqueous ophthalmic solutiondescribed herein, such as an aqueous ophthalmic solution described inSection II, to reduce pupil diameter in a patient.

The reduction in pupil diameter can be characterized according to, forexample, the percent reduction in pupil diameter and size of the pupilmeasured under certain light conditions. Accordingly, in certainembodiments, the reduction in pupil diameter under mesopic conditions isat least 5% compared to the pupil diameter of the patient under the samemesopic conditions but not having received the aqueous ophthalmicsolution. In certain other embodiments, the reduction in pupil diameterunder mesopic conditions is at least 10% compared to the pupil diameterof the patient under the same mesopic conditions but not having receivedthe aqueous ophthalmic solution. In certain other embodiments, thepatient experiences a reduction in pupil diameter of at least 0.5 mmwhen measured under mesopic conditions relative to the diameter of thepatient's pupil under the same mesopic conditions but not havingreceived the aqueous ophthalmic solution. In certain other embodiments,the patient experiences a reduction in pupil diameter ranging from about0.6 mm to about 3 mm, about 0.6 mm to about 2.5 mm, or about 0.6 mm toabout 2 mm when measured under mesopic conditions relative to thediameter of the patient's pupil under the same mesopic conditions butnot having received the aqueous ophthalmic solution. In certain otherembodiments, the patient experiences a reduction in pupil diameterranging from about 0.6 mm to about 1.2 mm when measured under mesopicconditions relative to the diameter of the patient's pupil under thesame mesopic conditions but not having received the aqueous ophthalmicsolution. In yet other embodiments, the patient's pupil is reduced to adiameter of about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 4mm to about 5 mm, about 4 mm to about 6 mm, or about 4 mm to about 7 mmunder mesopic conditions due to the aqueous ophthalmic solution. Incertain embodiments, the patient's pupil is reduced to a diameter ofabout 4 mm to about 6 mm under mesopic conditions due to the aqueousophthalmic solution.

In certain other embodiments, the reduction in pupil diameter underscotopic conditions is at least 5% compared to the pupil diameter of thepatient under the same scotopic conditions but not having received theaqueous ophthalmic solution. In certain other embodiments, the reductionin pupil diameter under scotopic conditions is at least 10% compared tothe pupil diameter of the patient under the same scotopic conditions butnot having received the aqueous ophthalmic solution. In certain otherembodiments, the patient experiences a reduction in pupil diameter of atleast 0.5 mm when measured under scotopic conditions relative to thediameter of the patient's pupil under the same scotopic conditions butnot having received the aqueous ophthalmic solution. In certain otherembodiments, the patient experiences a reduction in pupil diameterranging from about 0.6 mm to about 3 mm, about 0.6 mm to about 2.5 mm,or about 0.6 mm to about 2 mm when measured under scotopic conditionsrelative to the diameter of the patient's pupil under the same scotopicconditions but not having received the aqueous ophthalmic solution. Incertain other embodiments, the patient experiences a reduction in pupildiameter ranging from about 0.6 mm to about 1.2 mm when measured underscotopic conditions relative to the diameter of the patient's pupilunder the same scotopic conditions but not having received the aqueousophthalmic solution. In yet other embodiments, the patient's pupil isreduced to a diameter of about 3 mm to about 5 mm, about 3 mm to about 6mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, or about 4 mm toabout 7 mm under scotopic conditions due to the aqueous ophthalmicsolution. In certain embodiments, the patient's pupil is reduced to adiameter of about 4 mm to about 6 mm under scotopic conditions due tothe aqueous ophthalmic solution.

Methods of Reducing Aberrant Focus of Scattered Light Rays

One aspect of the invention provides a method of reducing an aberrantfocus of scattered light rays in a patient's eye. The method comprisesadministering to the eye of a patient in need thereof an effectiveamount of an aqueous ophthalmic solution, such as an aqueous ophthalmicsolution described in Section II, to reduce aberrant focus of scatteredlight rays in the patient's eye.

General Considerations for Therapeutic Methods

The aqueous ophthalmic solution can be administered according to adosing regimen. For example, in certain embodiments, the aqueousophthalmic solution is administered at the bedtime of the patient.

The therapeutic method can be further characterized according to theincidence and severity of any adverse side effects associated withadministration of the aqueous ophthalmic solution to the patient.Desirably the aqueous ophthalmic solution provides a therapeutic benefit(e.g., improvement in visual performance) while minimizing the impactand/or occurrence of any adverse side effects, such as eye rednesssometimes associated with administration of the aqueous ophthalmicsolution to the eye of a patient. The degree of eye redness can beevaluated and characterized using procedures described in theliterature, such as the Cornea and Contact Lens Research Unit (CCLRU)Redness Grading Scale developed by the School of Optometry, Universityof New South Wales. See, for example, Terry et al. in Optom. Vis. Sci.(1993) vol. 70, pages 234-243; and Pult et al. in Ophthal. Physiol. Opt.(2008) vol. 28, pages 13-20. The CCLRU Redness Grading Scale evaluateseye redness on a four-point scale: (0) no eye redness, (1) very slighteye redness, (2) slight eye redness, (3) moderate eye redness, and (4)severe eye redness.

In certain embodiments, the method results in an increase in eye rednessof no more than two grades measured by the CCLRU Redness Grading Scale.In certain embodiments, the method results in an increase in eye rednessof no more than three grades measured by the CCLRU Redness GradingScale. In certain embodiments, the method results in an increase in eyeredness of no more than one grade when measured using the CCLRU RednessGrading Scale eight hours after administration of the aqueous ophthalmicsolution. In certain embodiments, the method results in an increase ineye redness of no more than one grade when measured using the CCLRURedness Grading Scale six hours after administration of the aqueousophthalmic solution. In certain embodiments, the method results in anincrease in eye redness of no more than two grades when measured usingCCLRU Redness Grading Scale two hours after administration of theaqueous ophthalmic solution. In certain other embodiments, any eyeredness in the patient due to administration of the aqueous ophthalmicsolution has subsided within eight hours after administration of theaqueous ophthalmic solution to the patient. In certain otherembodiments, any eye redness in the patient due to administration of theaqueous ophthalmic solution has subsided within six hours afteradministration of the aqueous ophthalmic solution to the patient.

The therapeutic method can also be characterized according to themagnitude of the improvement in visual acuity afforded by the aqueousophthalmic solution. For example, in certain embodiments, the methodresults in an improvement in visual acuity characterized by at least atwo-line improvement in the patient's vision measured using a Snellenchart.

In certain embodiments, the patient is a human.

In certain embodiments, the aqueous ophthalmic solution is one of thegeneric or specific aqueous ophthalmic solutions described in SectionII.

The description above describes multiple embodiments relating totherapeutic methods using aqueous ophthalmic solution. The patentapplication specifically contemplates all combinations of theembodiments. For example, the invention contemplates improving visualacuity under scotopic conditions using an aqueous ophthalmic solutioncomprising phentolamine mesylate.

Additional Considerations

Actual dosage levels of the active ingredients in the aqueous ophthalmicsolution of this invention may be varied so as to obtain an amount ofthe active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the aqueous ophthalmic solution of the presentinvention employed or salt thereof, the route of administration, thetime of administration, the rate of excretion or metabolism of theparticular compound being employed, the rate and extent of absorption,the duration of the treatment, other drugs, compounds and/or materialsused in combination with the aqueous ophthalmic solution employed, theage, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medicalarts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the aqueous ophthalmicsolution required. For example, the physician or veterinarian couldstart doses of the aqueous ophthalmic solution at levels lower than thatrequired in order to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved.

If desired, the effective daily dose of the aqueous ophthalmic solutionmay be administered as one or two sub-doses administered separately atappropriate intervals throughout the day (or week), optionally, in unitdosage forms.

IV. KITS FOR USE IN MEDICAL APPLICATIONS

Another aspect of the invention provides a kit for medical therapy Thekit comprises: i) instructions for improving vision in a patient, suchas improving visual performance); and ii) an aqueous ophthalmic solutiondescribed herein. The kit may comprise one or more unit dosage formscontaining an amount of the aqueous ophthalmic solution described hereineffective for improving vision in the patient.

The description above describes multiple aspects and embodiments of theinvention, including aqueous ophthalmic solutions, methods of using theaqueous ophthalmic solutions, and kits. The patent applicationspecifically contemplates all combinations and permutations of theaspects and embodiments.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following example, which is includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and is not intended to limit the invention.

Example 1 Stability Analysis of Aqueous Solution Containing 1% (w/v)Phentolamine Mesylate

The purpose of this experiment was to evaluate the stability of aqueoussolutions containing phentolamine mesylate over a range of temperatures.

Experimental Design

Phentolamine mesylate (1.0% w/v) was obtained from SpectrumPharmaceuticals. The HPLC analytical method for analysis of theformulations was developed by Newport Scientific, Inc.

The assay for API, impurities and degradants was performed usingAtlantis HILIC 4.6 mm×250 mm×5 μm column. The injection volume was 10μL. Mobile phase A: 10 mM HCOONH₄ in water (12%). HCOONH₄ (10 mmol, 630mg) was dissolved in 950 mL water. The pH was adjusted to 3.0 byaddition of formic acid. The volume was then completed to 1 L by addingwater (50 mL). Mobile phase B: Acetonitrile (88%). The temperature was35° C., the flow rate was 1 mL/min, the injection volume was 10 μL, andthe sample/standard concentration was 100 μg/mL.

Each sample was well shaken and then 0.5 to 1.0 mL were transferred intoa clear test tube and physical appearance recorded.

Bottles containing 5.0 mL of 1.0% w/v phentolamine mesylate ophthalmicsolution were stored at 2-8° C., 25° C., 40° C., and 60° C. For eachtested time point, two bottles were used. Before testing, all sampleswere allowed to equilibrate to room temperature. Immediately prior toconducting each test, each sample was vigorously shaken. Then, assay forAPI, impurities and degradants was performed according to the methoddescribed above and the physical appearance of the sample wasdetermined. Also, the pH of the sample was determined and measured induplicate to ensure that there is no drift.

A final report was generated upon completion of the protocol.

Phentolamine mesylate (1.0% w/v) was tested for stability in water overthe course of four weeks at the following temperatures: 2-8° C., 25° C.,40° C., and 60° C.

Results

The results of this experiment are provided in Tables 1A-1D. Theabbreviation “N/A” indicates that no data are available.

TABLE 1A AQUEOUS SOLUTION OF 1% (W/V) PHENTOLAMINE MESYLATE (PM) STOREDAT 2-8° C. Percent of Initial Phentolamine Time Concentration PMConcentration Mesylate Area (weeks) (mg/mL) Remaining (%) Percent (%) pH0 10.520 100.0 99.63 5.001 1 N/A N/A N/A N/A 2 N/A N/A N/A N/A 4  9.860 93.4 99.65 6.460

TABLE 1B 1% (W/V) PHENTOLAMINE MESYLATE (PM) SOLUTION STORED AT 25° C.Percent of Initial Phentolamine Time Concentration PM ConcentrationMesylate Area (weeks) (mg/mL) Remaining (%) Percent (%) pH 0 10.520100.0 99.63 5.001 1 N/A N/A N/A N/A 2 N/A N/A N/A N/A 4  9.630  91.6098.85 6.360

TABLE 1C 1% (W/V) PHENTOLAMINE MESYLATE (PM) SOLUTION STORED AT 40° C.Percent of Initial Phentolamine Time Concentration PM ConcentrationMesylate Area (weeks) (mg/mL) Remaining (%) Percent (%) pH 0 10.520 100.0  99.63 5.001 1 N/A N/A N/A N/A 2 9.913 94.20 99.41 5.034 4 9.37089.10 97.20 6.400

TABLE 1D 1% (W/V) PHENTOLAMINE MESYLATE (PM) SOLUTION STORED AT 60° C.Percent of Initial Phentolamine Time Concentration PM ConcentrationMesylate Area (weeks) (mg/mL) Remaining (%) Percent (%) pH 0 10.520100.0 99.63 5.001 1 8.723 87.20 89.53 6.006 2 8.544 81.20 91.86 5.406

As demonstrated by the data in Tables 1A-1D, phentolamine mesylatedegrades rapidly in water over the brief period of 4 weeks across a widerange of temperatures.

Example 2 Stability of 1% (w/v)Phentolamine Mesylate and 5% (w/v)Mannitol in Water

The purpose of this experiment was to examine stability of an aqueoussolution containing phentolamine mesylate (1.0% w/v) and mannitol (5%w/v) at three temperatures: 2-8° C., 25° C., and 40° C. For clarity, thesolutions tested in this example did not contain a buffer.

Experimental Design and Methods

Phentolamine mesylate (1.0% w/v) was obtained from SpectrumPharmaceuticals. The HPLC analytical method for analysis of theformulations was developed by Newport Scientific, Inc.

The assay for API, impurities and degradants was performed usingAtlantis HILIC 4.6 mm×250 mm×5 μm column. The injection volume was 10μL. Mobile phase A: 10 mM HCOONH₄ in water (12%). HCOONH₄ (10 mmol, 630mg) was dissolved in 950 mL water. The pH was adjusted to 3.0 byaddition of formic acid. The volume was then completed to 1 L by addingwater (50 mL). Mobile phase B: Acetonitrile (88%). The temperature was35° C., the flow rate was 1 mL/min, the injection volume was 10 μL andthe sample/standard concentration was 100 μg/mL.

Each sample was well shaken and then 0.5 to 1.0 mL were transferred intoa clear test tube and physical appearance recorded.

Bottles containing 5.0 mL of 1.0% w/v phentolamine mesylate ophthalmicsolution were stored at 2-8° C., 25° C., and 40° C. For each tested timepoint, two bottles were used. Before testing, all samples were allowedto equilibrate to room temperature. Immediately prior to conducting eachtest, each sample was vigorously shaken. Then, assay for API, impuritiesand degradants was performed according to the method described above andthe physical appearance of the sample was determined. Also, the pH ofthe sample was determined and measured in duplicate to ensure that thereis no drift.

A final report was generated upon completion of the protocol.

An aqueous phentolamine mesylate (1.0% w/v) solution containing mannitol(5% w/v) was tested for stability over the course of twelve months atthe following temperatures: 2-8° C., 25° C., and 40° C. For comparisonpurposes, an EDTA-containing solution was also prepared and tested. TheEDTA-containing solution was identical to the above solution, exceptthat the solution also contained 0.01% w/v EDTA.

Results

The results of this experiment are demonstrated in Tables 2A-2F and inFIGS. 1A-1C.

TABLE 2A 1% (W/V) PHENTOLAMINE MESYLATE (PM) AND 5% (W/V) MANNITOLSOLUTION STORED AT 2-8° C. Percent of Phentolamine Time ConcentrationInitial PM Mesylate Area (months) (mg/mL) Concentration (%) Percent (%)pH 0 10.01 100.0 99.65 5.17 1 10.17 101.64 99.53 4.91 2 10.00 99.8499.76 4.76 3 9.79 97.84 99.73 4.82 4 10.02 100.07 99.70 4.92 6 10.18101.67 99.57 5.03 9 10.02 100.14 99.54 5.02 12 10.34 103.37 99.65 5.03

TABLE 2B 1% (W/V) PHENTOLAMINE MESYLATE (PM) AND 5% (W/V) MANNITOLSOLUTION STORED AT 25° C., 40% RELATIVE HUMIDITY (RH) Percent ofPhentolamine Time Concentration Initial PM Mesylate Area (months)(mg/mL) Concentration (%) Percent (%) pH 0 10.01 100.0 99.65 5.17 110.25 102.38 99.41 4.57 2 9.84 98.33 99.66 4.49 3 9.88 98.68 99.56 4.854 10.24 102.24 99.3 4.52 6 10.22 102.09 99.28 4.35 9 9.89 98.80 99.084.80 12 10.63 106.26 99.03 4.50

TABLE 2C 1% (W/V) PHENTOLAMINE MESYLATE (PM) AND 5% (W/V) MANNITOLSOLUTION STORED AT 40° C. Percent of Phentolamine Time ConcentrationInitial PM Mesylate Area (months) (mg/mL) Concentration (%) Percent (%)pH 0 10.01 100.0 99.65 5.17 0.5 9.90 98.88 99.59 5.95 1 9.84 98.29 99.364.50 2 9.85 98.34 99.36 4.16 3 9.70 96.91 99.20 4.23 4 9.99 99.80 99.184.05

TABLE 2D 1% (W/V) PHENTOLAMINE MESYLATE (PM), 5% (W/V) MANNITOL AND EDTASOLUTION STORED AT 2-8° C. Percent of Phentolamine Time ConcentrationInitial PM Mesylate Area (months) (mg/mL) Concentration (%) Percent (%)pH 0 10.01 100.0 99.66 5.78 1 10.05 100.42 99.77 4.77 2 10.02 100.0899.75 4.68 3 9.80 97.95 99.75 4.83 4 10.01 100.02 99.49 4.60 6 10.12101.07 99.45 4.66 9 10.05 100.39 99.60 4.85 12 10.20 102.01 99.57 4.71

TABLE 2E 1% (W/V) PHENTOLAMINE MESYLATE (PM), 5% (W/V) MANNITOL AND EDTASOLUTION STORED AT 25° C., 40% RELATIVE HUMIDITY (RH) Percent ofPhentolamine Time Concentration Initial PM Mesylate Area (months)(mg/mL) Concentration (%) Percent (%) pH 0 10.01 100.0 99.66 5.78 110.19 101.78 99.53 4.64 2 9.93 99.19 99.68 4.48 3 9.81 98.01 99.42 4.874 10.18 101.73 99.44 4.63 6 10.15 101.44 99.37 4.08 9 10.12 101.08 98.984.25 12 10.55 105.46 99.01 4.26

TABLE 2F 1% (W/V) PHENTOLAMINE MESYLATE (PM), 5% (W/V) MANNITOL AND EDTASOLUTION STORED AT 40° C. Percent of Phentolamine Time ConcentrationInitial PM Mesylate Area (months) (mg/mL) Concentration (%) Percent (%)pH 0 10.01 100.0 99.66 5.78 0.5 9.90 98.88 99.56 4.70 1 9.79 97.83 99.394.56 2 9.74 97.34 99.41 4.15 3 10.01 99.99 99.14 4.39 4 9.93 99.23 98.984.51

For comparison purposes, Applicants have compared these results with theresults obtained for a representative prior art formulation ofphentolamine mesylate containing a metal chelator (Formulation #1 inExample 2 of U.S. Pat. No. 7,229,630 B2 (the '630 patent)) stored at 25°C. This prior art formulation is referred to as the “Nova Formulation”and contains 0.1 mg/mL (i.e., 0.01% w/v) phentolamine mesylate, 0.5mg/mL (i.e., 0.05% w/v) disodium EDTA, 5% w/v d-mannitol, 10 mM sodiumacetate, and water. Data points for the Nova Formulation were taken fromTables VII-IX of the '630 patent.

The terms “Phentolamine Area Percent” and “area percent” refer to anHPLC method of determining purity of the recovered phentolamine at eachgiven time point by calculating the peak area. It is well known in theart how to calculate area percent.

FIG. 1A is a line graph of percentage of initial concentration ofphentolamine mesylate remaining vs time. The five lines in the graphcorrespond to the five solutions tested: (1) solution containingphentolamine mesylate and mannitol (abbreviated P+M) stored at 2-8° C.;(2) solution containing phentolamine mesylate and mannitol (abbreviatedP+M) stored at 25° C.; (3) solution containing phentolamine mesylate andmannitol (abbreviated P+M) stored at 40° C.; (4) the Nova Formulationstored at 25° C. (abbreviated as “Nova 25C”); and (5) solutioncontaining phentolamine mesylate, mannitol, and EDTA stored at 25° C.

FIG. 1B is a line graph of area percent of phentolamine mesylate vstime. The five lines in the graph correspond to the five solutionstested: (1) solution containing phentolamine mesylate and mannitol(abbreviated P+M) stored at 2-8° C.; (2) solution containingphentolamine mesylate and mannitol (abbreviated P+M) stored at 25° C.;(3) solution containing phentolamine mesylate and mannitol (abbreviatedP+M) stored at 40° C.; (4) the Nova Formulation stored at 25° C.(abbreviated as “Nova 25C”); and (5) solution containing phentolaminemesylate, mannitol, and EDTA stored at 25° C.

FIG. 1C is a line graph of pH of the phentolamine mesylate solution vstime. The five lines in the graph correspond to the five solutionstested: (1) solution containing phentolamine mesylate and mannitol(abbreviated P+M) stored at 2-8° C.; (2) solution containingphentolamine mesylate and mannitol (abbreviated P+M) stored at 25° C.;(3) solution containing phentolamine mesylate and mannitol (abbreviatedP+M) stored at 40° C.; (4) the Nova Formulation stored at 25° C.(abbreviated as “Nova 25C”); and (5) solution containing phentolaminemesylate, mannitol, and EDTA stored at 25° C.

As the data in Tables 2A-2F and FIGS. 1A-1B indicated, the solutioncontaining 1% (w/v) phentolamine mesylate and 5% mannitol is very stableover time as measured by both percent initial concentration and areapercent. In fact, the formulation has superior stability thanconventional Nova 25C formulation containing a metal chelator (EDTA).The absence of EDTA in the inventive formulation did not have a negativeeffect on either percentage of initial concentration of phentolaminemesylate or area percent of phentolamine.

FIG. 1C shows that the pH of the tested formulations at 25° C. and 40°C. tends to slightly decline over time. These tested formulations didnot include a buffer.

Example 3 Stability of 0.01% w/v and 2.0% w/v Phentolamine Mesylate and5% w/v Mannitol in Water

The purpose of this experiment was to examine the stability of aqueoussolutions containing 0.01% w/v or 2.0% w/v phentolamine mesylate and 5%w/v mannitol (without a buffer) at two temperatures (25° C. and 40° C.)to determine if the concentration of phentolamine mesylate effectsstability.

Experimental Design and Methods

Aqueous solutions containing phentolamine mesylate (0.01% or 2.0% w/v)and mannitol (5% w/v) were tested for stability over the course oftwelve months at 25° C. and 40° C.

The experimental design and methods were substantially similar to thoseof the experiment described in Examples 1 and 2 above.

Results

The results of this experiment are provided in Tables 3A-D and in FIGS.2A-2C.

TABLE 3A 2% (W/V) PHENTOLAMINE MESYLATE (PM) AND 5% (W/V) MANNITOLSOLUTIONS STORED AT 25° C., 40% RH Percent of Phentolamine TimeConcentration Initial PM Mesylate Area (months) (mg/mL) Concentration(%) Percent (%) pH 0 19.85 100.0 99.64 4.42 1 20.03 100.88 99.65 4.75 220.78 104.67 99.66 4.29 3 20.95 105.52 99.68 4.30

TABLE 3B 2% (W/V) PHENTOLAMINE MESYLATE (PM) AND 5% (W/V) MANNITOLSOLUTIONS STORED AT 40° C. Percent of Phentolamine Time ConcentrationInitial PM Mesylate Area (months) (mg/mL) Concentration (%) Percent (%)pH 0 19.85 100.0 99.64 4.42 1 19.25 96.96 99.64 4.32 2 20.49 103.2299.50 4.09 3 20.93 105.43 99.44 4.02

TABLE 3C 0.01% (W/V) PHENTOLAMINE MESYLATE (PM) AND 5% (W/V) MANNITOlSOLUTIONS STORED AT 25° C. Percent of Phentolamine Time ConcentrationInitial PM Mesylate Area (months) (mg/mL) Concentration (%) Percent (%)pH 0 0.093 100.0 99.53 4.18 1 0.100 106.88 99.67 4.81 2 0.098 104.7698.76 4.04 3 0.098 105.28 99.14 3.95

TABLE 3D 0.01% (W/V) PHENTOLAMINE MESYLATE (PM) AND 5% (W/V) MANNITOLSOLUTIONS STORED AT 40° C. Percent of Phentolamine Time ConcentrationInitial PM Mesylate Area (months) (mg/mL) Concentration (%) Percent (%)pH 0 0.093 100.0 99.53 4.18 1 0.095 102.13 99.54 4.28 2 0.097 103.7499.47 4.32 3 0.097 104.13 99.24 4.39

FIG. 2A shows a line graph of percent of initial concentration ofphentolamine mesylate remaining vs time. FIG. 2B shows a line graph ofarea percent of phentolamine mesylate vs time. FIG. 2C shows a linegraph of pH of the phentolamine mesylate solution vs time. In each ofFIGS. 2A, 2B, and 2C, the four lines in the graphs correspond to thefour solutions tested: (1) solution containing phentolamine mesylate(0.01% w/v) and mannitol (abbreviated 0.01% P) stored at 25° C.; (2)solution containing phentolamine mesylate (0.01% w/v) and mannitol(abbreviated 0.1% P) stored at 40° C.; (3) solution containingphentolamine mesylate (2% w/v) and mannitol (abbreviated 2% P) stored at25° C.; (4) solution containing phentolamine mesylate (2% w/v) andmannitol (abbreviated 2% P) stored at 40° C.

As the data in Tables 3A-3D and FIGS. 2A-2B show, there is nosignificant difference in the stability profile between the solutionstested containing 0.01% w/v and 2.0% w/v phentolamine mesylate. The datain FIG. 2C shows that the pH of the solutions at 25° C. and 40° C.declined slightly over time. These tested solutions did not include abuffer.

Example 4 Stability of 1% (W/V) Phentolamine Mesylate, 4% (W/V) Mannitoland 3 Mm Sodium Acetate Buffer in Water

The purpose of this experiment was to examine whether adding a weakbuffer further stabilizes the phentolamine mesylate/mannitol solution bypreventing or reducing the slight decline in pH over time as observed innon-buffered solutions (See, Examples 2 and 3 above). Sodium acetate wasused as a weak buffer at a concentration of 3 mM. In one testedsolution, hydroxypropyl methylcellulose (HPMC) was added to thesolution. Stability of the solutions was tested at three temperatures:2-8° C., 25° C., and 40° C.

Experimental Design and Methods

An aqueous solution containing phentolamine mesylate (1.0% w/v),mannitol (4% w/v), and sodium acetate buffer (3 mM) with and withoutHPMC was tested for stability over the course of six months at thefollowing temperatures: 2-8° C., 25° C., and 40° C.

The experimental design and methods were substantially similar to thoseof the experiment described in Examples 1 and 2 above.

Results

The results of this experiment are shown in Tables 4A-4F and in FIGS.3A-3F.

TABLE 4A 1% (W/V) PHENTOLAMINE MESYLATE (PM), 4% (W/V) MANNITOL AND 3 mMSODIUM ACETATE BUFFER (NO HPMC) SOLUTION STORED AT 2-8° C. Percent ofPhentolamine Time Concentration Initial PM Mesylate Area (months)(mg/mL) Concentration (%) Percent (%) pH 0 9.65 100.0 98.73 4.81 3 10.59109.74 99.67 4.87 6 10.45 108.29 99.31 4.94

TABLE 4B 1% (W/V) PHENTOLAMINE MESYLATE (PM), 4% (W/V) MANNITOL AND 3 mMSODIUM ACETATE BUFFER (NO HPMC) SOLUTION STORED AT 25° C. Percent ofPhentolamine Time Concentration Initial PM Mesylate Area (months)(mg/mL) Concentration (%) Percent (%) pH 0 9.65 100.0 98.73 4.81 1 10.32106.94 99.32 4.97 2 10.55 109.33 99.49 4.94 3 10.54 109.22 99.34 4.89 610.4 107.77 98.90 4.78

TABLE 4C 1% (W/V) PHENTOLAMINE MESYLATE (PM), 4% (W/V) MANNITOL AND 3 mMSODIUM ACETATE BUFFER (NO HPMC) SOLUTION STORED AT 40° C. Percent ofPhentolamine Time Concentration Initial PM Mesylate Area (months)(mg/mL) Concentration (%) Percent (%) pH 0 9.65 100.0 98.73 4.81 2 weeks9.83 101.87 99.36 4.93 1 9.76 101.14 97.90 4.89 2 10.52 109.02 97.224.93 3 10.02 103.83 96.09 4.77 6 9.26 95.96 92.52 4.82

TABLE 4D 1% (W/V) PHENTOLAMINE MESYLATE (PM), 4% (W/V) MANNITOL AND 3 mMSODIUM ACETATE BUFFER (WITH HPMC) SOLUTION STORED AT 2-8° C. Percent ofPhentolamine Time Concentration Initial PM Mesylate Area (months)(mg/mL) Concentration (%) Percent (%) pH 0 9.56 100.0 98.73 4.86 3 10.12105.86 99.70 4.75 6 10.16 106.28 99.49 4.84

TABLE 4E 1% (W/V) PHENTOLAMINE MESYLATE (PM), 4% (W/V) MANNITOL AND 3 mMSODIUM ACETATE BUFFER (WITH HPMC) SOLUTION STORED AT 25° C. Percent ofPhentolamine Time Concentration Initial PM Mesylate Area (months)(mg/mL) Concentration (%) Percent (%) pH 0 9.56 100.0 98.73 4.86 1 10.02104.81 99.23 4.81 2 10.21 106.80 99.50 4.93 3 9.11 95.29 99.34 4.76 69.91 103.69 99.06 4.71

TABLE 4F 1% (W/V) PHENTOLAMINE MESYLATE (PM), 4% (W/V) MANNITOL AND 3 mMSODIUM ACETATE BUFFER (WITH HPMC) SOLUTION STORED AT 40° C. Percent ofPhentolamine Time Concentration Initial PM Mesylate Area (months)(mg/mL) Concentration (%) Percent (%) pH 0 9.56 100.0 98.73 4.86 2 weeks9.88 103.35 99.37 4.83 1 10.02 104.81 98.34 4.83 2 10.05 105.13 97.694.84 3 9.52 99.58 96.62 4.79 6 9.39 98.22 94.36 4.64

For comparison purposes, the results are compared with the resultsobtained for the Nova formulation stored at 25° C.

FIG. 3A shows a line graph of percentage of initial concentration ofphentolamine mesylate remaining at 25° C. vs time. FIG. 3B shows a linegraph of area percent of phentolamine mesylate vs time at 25° C. FIG. 3Cshows a line graph of pH of the phentolamine mesylate solution vs timeat 25° C. In each of FIGS. 3A to 3C, the four lines in the graphscorrespond to the four solutions tested: (1) phentolamine mesylate andmannitol (abbreviated P/M); (2) phentolamine mesylate, mannitol andacetate buffer without HPMC (abbreviated P/M/A); (3) phentolaminemesylate, mannitol and acetate buffer with HPMC (abbreviated P/M/A/H);and (4) the Nova Formulation (abbreviated “Nova”).

FIG. 3D shows a line graph of percentage of initial concentration ofphentolamine mesylate remaining at 40° C. vs time. FIG. 3E shows a linegraph of area percent of phentolamine mesylate vs time at 40° C. FIG. 3Fshows a line graph of pH of the phentolamine mesylate solution vs timeat 40° C. In each of FIGS. 3D to 3F, the four lines in the graphscorrespond to the four solutions tested: (1) a solution containingphentolamine mesylate and mannitol (abbreviated P/M); (2) a solutioncontaining phentolamine mesylate, mannitol, and acetate buffer withoutHPMC (abbreviated P/M/A); (3) a solution containing phentolaminemesylate, mannitol and acetate buffer with HPMC (abbreviated P/M/A/H);and (4) the Nova Formulation (abbreviated “Nova”).

FIG. 3G shows a line graph of percent of initial concentration ofphentolamine mesylate remaining vs time for solutions stored at 2-8° C.FIG. 3H shows a line graph of area percent of phentolamine mesylate vstime for solutions stored at 2-8° C. FIG. 3I shows a line graph of pH ofthe phentolamine mesylate solution vs time for solutions stored at 2-8°C. In each of FIGS. 3G to 31, the four lines in the graphs correspond tothe four solutions tested: (1) a solution containing phentolaminemesylate and mannitol (abbreviated P/M); (2) a solution containingphentolamine mesylate, mannitol, and acetate buffer without HPMC(abbreviated P/M/A); (3) a solution containing phentolamine mesylate,mannitol and acetate buffer with HPMC (abbreviated P/M/A/H); and (4) theNova Formulation (abbreviated “Nova”).

As the data in Tables 4A-4F and FIGS. 3A-3I shows, both bufferedformulations (with HPMC and without HPMC) are stable over time anddemonstrate better stability than the conventional Nova formulation at2-8° C., 25° C., and 40° C. Further, the pH of both buffered solutionsdeclines only slightly over time.

In addition, a mildly buffered solution at pH of about 4.8 is closer tothe physiologic pH of the eye than the strongly buffered Novaformulation (pH of about 3.7-3.8). The inventive formulations are alsomore comfortable because the mild buffer permits the rapid equilibrationof pH in the cornea and does not promote stinging or watering of the eyeupon application. In contrast, applying a more strongly bufferedsolution at a pH of about 3.7-3.8 would cause significant stinging andwould not be comfortable for the subject receiving the solution.

Example 5 Stability Analysis of Phentolamine Mesylate Aqueous OphthalmicSolutions

Aqueous ophthalmic solutions containing mannitol (4% w/v), sodiumacetate (3 mM) and either 0% w/v, 0.5% w/v, or 1% w/v phentolaminemesylate where stored for up to nine months at 5° C., 25° C., or 40° C.The pH of the solution and the amount of phentolamine mesylate in thesolution was determined at the start of the experiment and atthree-month intervals. Experimental results are shown in Tables 1 and 2below. These results indicate that the phentolamine mesylate solutionhas good stability.

TABLE 1 PERCENTAGE OF INITIAL PHENTOLAMINE MESYLATE REMAINING UPONSTORAGE. Percent of Initial Phentolamine Mesylate Remaining (%) StorageTemperature (° C.) 5 25 40 Phentolamine Mesylate Concentration (% w/v)Storage Time (months) 1.0 0.5 1.0 0.5 1.0 0.5 0 100 100 100 100 100 1003 100 94 99 94 94 88 6 102 93 99 93 89 83 9 102 95 100 93 N/A N/A

TABLE 2 pH OF PHENTOLAMINE MESYLATE SOLUTIONS UPON STORAGE. pH of theSolution Storage Temperature (° C.) 5 25 40 Storage PhentolamineMesylate Time Concentration (% w/v) (months) 1.0 0.5 0 1.0 0.5 0 1.0 0.50 0 N/A N/A N/A 4.8 4.9 4.9 N/A N/A N/A 3 4.8 4.9 5 4.8 4.9 5 4.8 4.95.1 6 4.7 4.9 5 4.8 4.9 4.9 4.9 4.9   5 9 4.8 4.9 4.9 4.8 4.9 5 N/A N/AN/A

Example 6 Stability Analysis of Phentolamine Mesylate Aqueous OphthalmicSolutions

Aqueous ophthalmic solutions containing sodium acetate (3 mM),phentolamine mesylate (1% w/v), and either (i) mannitol (4% w/v), (ii)mannitol (2% w/v), (iii) glycerol (2% w/v), (iv) propylene glycol (2%w/v), or (v) mannitol (1% w/v) plus glycerol (1% w/v) were stored in lowdensity polyethylene containers at 57° C. for 14 days. The solutions hada pH of 5.0 at the start of the experiment. The amount of phentolaminemesylate in the solution was determined at the start of the experimentand at two-day intervals after the start of the experiment. Experimentalresults are shown in Table 1 below.

TABLE 1 PERCENTAGE OF INITIAL PHENTOLAMINE MESYLATE REMAINING UPONSTORAGE. Percentage of Initial of Phentolamine Mesylate (%) 1% (w/v) 2%(w/v) Mannitol + 4% (w/v) 2% (w/v) 2% (w/v) Propylene 1% (w/v) DayMannitol Mannitol Glycerol Glycol Glycerol 0 100.0 100.0 100.0 100.0100.0 2 101.5 102.1 103.4 100.5 100.9 7 96.4 94.2 94.7 94.7 90.8 14 93.489.7 89.7 88.8 89.3

Aqueous ophthalmic solutions containing sodium acetate (10 mM),phentolamine mesylate (1% w/v), and either (i) mannitol (4% w/v), (ii)glycerol (25% w/v), or (iiii) propylene glycol (25% w/v) were storedglass containers at 60° C. for 14 days. The solutions had a pH of 3.5 atthe start of the experiment. The amount of phentolamine mesylate in thesolution was determined at the start of the experiment and then after 2days, 7 days and 14 days after the start of the experiment. Experimentalresults are shown in Table 2 below.

TABLE 2 PERCENTAGE OF INITIAL PHENTOLAMINE MESYLATE REMAINING UPONSTORAGE. Percentage of Initial of Phentolamine Mesylate (%) 4% (w/v) 25%(w/v) 25% (w/v) Mannitol Glycerol Propylene Glycol Day Solution SolutionSolution 0 100.0 100.0 100.0 2 98.0 97.6 102.5 7 100.0 95.2 95.8 14 92.991.3 89.8

Example 7 Stability Analysis of Phentolamine Mesylate Aqueous OphthalmicSolutions

Aqueous ophthalmic solutions containing mannitol (4% w/v), sodiumacetate (3 mM) and either 0% w/v, 0.5% w/v, or 1% w/v phentolaminemesylate where stored for up to twenty-four months at (i) 5° C. atambient relative humidity or (ii) 25° C. at 40% relative humidity. Theophthalmic solutions were analyzed for appearance, pH, osmolality,phentolamine mesylate potency, amount of phentolamine mesylate relatedsubstances, amount of particulates, weight loss, and sterility.Experimental results are described below, where the abbreviation “RH”refers to relative humidity. The experimental results show that thephentolamine mesylate solutions have good stability upon storage fortwenty-four months at both (i) 5° C. at ambient relative humidity and(ii) 25° C. at 40% relative humidity.

A. Appearance

The appearance of the aqueous ophthalmic solutions and the appearance ofthe containers containing the aqueous ophthalmic solutions were analyzedat time points 1, 3, 6, 9, 12, 18, and 24 months after the start of theexperiment. Except as noted below, the aqueous ophthalmic solutions wereobserved to be clear and colorless at each time point measured:

-   -   For the 0.5% w/v phentolamine mesylate aqueous ophthalmic        solution stored at 25° C. at 40% relative humidity, the solution        was clear but slightly brown colored at time points 18 months        and 24 months.    -   For the 1.0% w/v phentolamine mesylate aqueous ophthalmic        solution stored at 25° C. at 40% relative humidity, the solution        was clear but contained a small brown fleck at the 12 month time        point due to spillage on the neck of the bottle during filing        operations that fell into the bottle during opening, and thus        not indicative of product or container failure.

Except as noted below, the container was observed to be intact, with noevidence of leaking or crusting, at each time point measured:

-   -   For the 1.0% w/v phentolamine mesylate aqueous ophthalmic        solution stored at 25° C. at 40% relative humidity, the        container was intact but brown crusting on the bottle was        observed due to spillage on the neck of the bottle during prior        filing operations.

B. Osmolality and pH

The osmolality and pH of the aqueous ophthalmic solutions is provided inTables 1-3 below.

TABLE 1 OSMOLALITY AND PH OF PLACEBO AQUEOUS OPHTHALMIC SOLUTION StoragePull Time Osmolality Conditions (months) pH (mOsm/kg) 5° C./ Initial 5.1234 Ambient RH 1 4.9 229 3 5.0 234 6 5.0 233 9 4.9 241 12 5.0 238 18 5.0234 24 5.0 234 25° C./40% RH 1 5.0 234 3 5.1 234 6 4.9 239 9 5.0 242 124.9 236 18 5.0 239 24 5.0 239

TABLE 2 OSMOLALITY AND PH OF 0.5% W/V PHENTOLAMINE MESYLATE AQUEOUSOPHTHALMIC SOLUTION Storage Pull Time Osmolality Conditions (months) pH(mOsm/kg) 5° C./ Initial 5.1 259 Ambient RH 1 5.0 261 3 4.9 256 6 4.9259 9 4.9 264 12 4.9 265 18 4.9 259 24 5.0 259 25° C./40% RH 1 5.0 263 34.9 263 6 4.9 263 9 4.9 274 12 5.0 257 18 4.9 264 24 5.0 262

TABLE 3 OSMOLALITY AND PH OF 1.0% W/V PHENTOLAMINE MESYLATE AQUEOUSOPHTHALMIC SOLUTION Storage Pull Time Osmolality Conditions (months) pH(mOsm/kg) 5° C./ Initial 5.0 287 Ambient RH 1 4.9 286 3 4.8 284 6 4.7286 9 4.8 292 12 4.8 287 25° C./40% RH 1 4.9 284 3 4.8 281 6 4.8 285 94.8 292 12 4.9 284 18 4.7 287 24 4.9 285

C. Phentolamine Mesylate Potency

The phentolamine mesylate potency of the aqueous ophthalmic solutions isprovided in Tables 4 and 5 below.

TABLE 4 PHENTOLAMINE MESYLATE POTENCY OF 0.5% W/V PHENTOLAMINE MESYLATEAQUEOUS OPHTHALMIC SOLUTION Storage Pull Time Potency Conditions(months) (% of Label Claim) 5° C./ Initial 104.0 Ambient RH 1 103.6 3101.5 6 101.7 9 102.9 12 100.7 18 102.6 24 100.9 25° C./40% RH 1 103.4 3101.4 6 100.6 9 100.8 12 98.5 18 98.7 24 96.6

TABLE 5 PHENTOLAMINE MESYLATE POTENCY OF 1.0% W/V PHENTOLAMINE MESYLATEAQUEOUS OPHTHALMIC SOLUTION Storage Pull Time Potency Conditions(months) (%) 5° C./ Initial 102.7 Ambient RH 1 103.2 3 101.9 6 104.0 9103.6 12 102.8 25° C./40% RH 1 103.6 3 100.9 6 101.0 9 101.8 12 98.6 1896.6 24 91.5

D. Amount of Phentolamine Mesylate Related Substances

The amount of phentolamine mesylate related substances identified byhigh-performance liquid chromatograph is provided in Tables 6 and 7below.

TABLE 6 AMOUNT OF PHENTOLAMINE MESYLATE RELATED SUBSTANCES IDENTIFIED IN0.5% W/V PHENTOLAMINE MESYLATE AQUEOUS OPHTHALMIC SOLUTION Amount ofRelated Storage Pull Time Substances (Percent Conditions (months) ofArea Under Curve) 5° C./ Initial 0.09 Ambient RH 1 0.10 3 0.21 6 0.18 90.26 12 0.17 18 0.17 24 0.19 25° C./40% RH 1 0.29 3 0.67 6 1.10 9 1.4012 1.92 18 2.85 24 3.64

TABLE 7 AMOUNT OF PHENTOLAMINE MESYLATE RELATED SUBSTANCES IDENTIFIED IN1.0% W/V PHENTOLAMINE MESYLATE AQUEOUS OPHTHALMIC SOLUTION Amount ofRelated Storage Pull Time Substances (Percent Conditions (months) ofArea Under Curve) 5° C./ Initial 0.14 Ambient RH 1 0.15 3 0.22 6 0.29 90.27 12 0.11 25° C./40% RH 1 0.26 3 0.51 6 0.95 9 0.95 12 1.70 18 2.1524 2.96

E. Amount of Particulates in Aqueous Ophthalmic Solutions

The amount of particulates in the aqueous ophthalmic solutions, asidentified by high-performance liquid chromatograph, is provided inTables 8-10 below.

TABLE 8 AMOUNT OF PARTICULATES IN PLACEBO AQUEOUS OPHTHALMIC SOLUTIONStorage Pull Time Particle Count (particles/mL) Conditions (months) ≧10μm ≧25 μm ≧50 μm 5° C./ Initial 6 0 0 Ambient RH 6 48 0 N/A 12 15 3 N/A24 1 0 0 25° C./40% RH 6 1 0 N/A 12 9 1 N/A 24 1 1 1

TABLE 9 AMOUNT OF PARTICULATES IN 0.5% W/V PHENTOLAMINE MESYLATE AQUEOUSOPHTHALMIC SOLUTION Storage Pull Time Particle Count (particles/mL)Conditions (months) ≧10 μm ≧25 μm ≧50 μm 5° C./ Initial 2 0 0 Ambient RH12 13 1 N/A 24 0 0 0 25° C./40% RH 6 1 0 N/A 12 42 4 N/A

TABLE 10 AMOUNT OF PARTICULATES IN 1.0% W/V PHENTOLAMINE MESYLATEAQUEOUS OPHTHALMIC SOLUTION Storage Pull Time Particle Count(particles/mL) Conditions (months) ≧10 μm ≧25 μm ≧50 μm 5° C./ Initial 10 0 Ambient RH 12 21 2 N/A 25° C./40% RH 6 3 0 N/A 12 48 2 N/A 24 3 2 2

F. Weight Loss for Aqueous Ophthalmic Solutions

Weight loss for the aqueous ophthalmic solutions (due to, for example,loss of water from the solution) was analyzed and results are providedin Tables 11-13 below. Five bottles of each type of aqueous ophthalmicsolution (i.e., five bottles of placebo, five bottles of 0.5% w/vphentolamine mesylate, and five bottles of 1.0% w/v phentolaminemesylate) were analyzed.

TABLE 11 WEIGHT LOSS FOR PLACEBO AQUEOUS OPHTHALMIC SOLUTION TimeStorage Point Weight Loss (% Lost from Initial) Conditions (Months)Bottle 1 Bottle 2 Bottle 3 Bottle 4 Bottle 5 5° C./ 1 −0.1 −0.1 −0.1−0.1 −0.1 Ambient RH 3 0.0 −0.1 −0.1 −0.1 −0.1 6 −0.1 −0.1 −0.1 −0.1−0.1 9 0.0 0.0 0.0 0.0 0.0 12 0.1 0.0 0.0 0.0 0.0 18 −0.1 −0.1 −0.1 −0.1−0.1 24 0.0 0.0 0.0 0.0 0.0 25° C./ 1 −0.2 −0.2 −0.2 −0.2 −0.2 40% RH 30.0 0.0 0.0 0.0 0.0 6 −0.1 −0.1 0.0 −0.1 −0.1 9 0.0 0.0 −0.1 0.0 −0.1 120.0 −0.1 −0.1 0.0 −0.1 18 −0.1 −0.1 −0.1 −0.1 −0.1 24 0.0 −0.1 0.0 0.00.0

TABLE 12 WEIGHT LOSS FOR 0.5% w/v PHENTOLAMINE MESYLATE AQUEOUSOPHTHALMIC SOLUTION Storage Time Point Weight Loss (% Lost from Initial)Conditions (Months) Bottle 1 Bottle 2 Bottle 3 Bottle 4 Bottle 5 5° C./1 −0.1 −0.1 −0.1 −0.3 −0.2 Ambient RH 3 −0.1 −0.1 −0.1 −0.1 −0.1 6 −0.1−0.1 −0.1 −0.1 −0.1 9 0.0 0.0 0.0 0.0 0.0 12 0.0 0.0 0.0 0.0 0.0 18 −0.1−0.1 −0.1 −0.1 −0.2 24 0.0 0.0 0.0 0.0 0.0 25° C./ 1 −0.2 −0.1 −0.2 −0.1−0.1 40% RH 3 −0.5 −0.1 −0.1 0.0 −0.1 6 −0.9 −0.1 −0.1 −0.1 −0.1 9 −1.30.0 0.0 0.0 0.0 12 −1.9 0.0 −0.1 0.0 0.0 18 −2.6 −0.1 −0.1 −0.1 −0.1 24−2.9 −0.1 0.0 −0.1 0.0

TABLE 13 WEIGHT LOSS FOR 1.0% w/v PHENTOLAMINE MESYLATE AQUEOUSOPHTHALMIC SOLUTION Storage Time Point Weight Loss (% Lost from Initial)Conditions (Months) Bottle 1 Bottle 2 Bottle 3 Bottle 4 Bottle 5 50° C./1 −0.2 −0.3 −0.1 −0.1 −0.1 Ambient RH 3 0.0 0.0 0.0 0.0 0.0 6 −0.1 −0.1−0.1 −0.1 −0.1 9 0.0 0.0 0.0 0.0 0.0 12 0.1 0.0 0.0 0.0 0.0 25° C./ 1−0.1 −0.1 −0.1 −0.4 −0.3 40% RH 3 0.0 0.0 0.0 0.0 0.0 6 −0.1 −0.1 −0.1−0.1 −0.1 9 0.0 0.0 0.0 0.0 0.0 12 0.0 0.0 0.0 0.0 −0.1 18 −0.1 −0.1−0.1 −0.1 −0.1 24 0.0 −0.1 0.0 0.0 0.0

G. Sterility of Aqueous Ophthalmic Solutions

Aqueous ophthalmic solutions were analyzed for sterility for up to 24months at 5° C./ambient relative humidity and at 25° C./40% relativehumidity, except for the 1.0% w/v phentolamine mesylate aqueousophthalmic solutions which was stored at 5° C./ambient relative humiditywhich was analyzed for analyzed for only 12 months. No microbial growthwas observed for any of the aqueous ophthalmic solutions over theduration of the test.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. An aqueous ophthalmic solution free of a chelating agent, comprising:a. about 0.1% (w/v) to about 4% (w/v) of phentolamine or apharmaceutically acceptable salt thereof; b. about 1% (w/v) to about 6%(w/v) of at least one polyol compound having a molecular weight lessthan 250 g/mol; c. about 0.1 mM to about 10 mM of at least one buffer;and d. water; wherein the solution has a pH in the range of 4.0 to 7.5and does not contain a chelating agent.
 2. The solution of claim 1,wherein the at least one polyol compound is mannitol, glycerol,propylene glycol, ethylene glycol, sorbitol, or xylitol.
 3. The solutionof claim 1, wherein the at least one polyol compound is mannitol. 4-8.(canceled)
 9. The solution of claim 1, wherein the solution comprisesfrom about 2% (w/v) to about 5% (w/v) of the at least one polyolcompound.
 10. The solution claim 1, wherein the solution comprises fromabout 3.5% (w/v) to about 4.5% (w/v) of the at least one polyolcompound.
 11. The solution of claim 1, wherein the solution comprisesabout 4% (w/v) of the at least one polyol compound. 12-16. (canceled)17. The solution of claim 1, further comprising a cellulose agent.18-20. (canceled)
 21. The solution of claim 1, wherein the buffer ispresent at a concentration in the range of about 2 mM to about 4 mM. 22.The solution of claim 1, wherein the buffer is present at aconcentration of about 3 mM.
 23. The solution of claim 1, wherein thebuffer comprises an alkali metal alkylcarboxylate.
 24. The solution ofclaim 1, wherein the buffer comprises an alkali metal acetate.
 25. Thesolution of claim 1, wherein the buffer comprises sodium acetate. 26.The solution of claim 1, wherein the solution has a pH in the range of4.5 to 6.0.
 27. The solution of claim 1, wherein the solution has a pHin the range of 4.7 to 5.1.
 28. The solution of claim 1, wherein thesolution comprises from about 0.5% (w/v) to about 2% (w/v) ofphentolamine or a pharmaceutically acceptable salt thereof.
 29. Thesolution of claim 1, wherein the solution comprises about 1% (w/v) ofphentolamine or a pharmaceutically acceptable salt thereof.
 30. Thesolution of claim 1, wherein the solution comprises from about 0.1%(w/v) to about 4% (w/v) of phentolamine mesylate.
 31. The solution ofclaim 1, wherein the solution comprises from about 0.25% (w/v) to about2% (w/v) of phentolamine mesylate.
 32. The solution of claim 1, whereinthe solution comprises from about 0.25% (w/v) to about 1% (w/v) ofphentolamine mesylate.
 33. The solution of claim 1, wherein the solutioncomprises about 1% (w/v) of phentolamine mesylate.
 34. The solution ofclaim 1, further comprising one or more of a preservative, antioxidant,viscosity modifying agent, stabilizing agent, tonicity modifier, cornealpermeation enhancing agent, or surfactant.
 35. An aqueous ophthalmicsolution free of a chelating agent, comprising: a. about 0.25% (w/v) toabout 2% (w/v) of phentolamine mesylate; b. about 1% (w/v) to about 6%(w/v) of at least one polyol compound selected from the group consistingof is mannitol, glycerol, and propylene glycol; c. about 1 mM to about 6mM of an alkali metal acetate; and d. water; wherein the solution has apH in the range of 4.5 to 5.5 and does not contain a chelating agent.36. The solution of claim 35, wherein the solution comprises from about0.25% (w/v) to about 1% (w/v) of phentolamine mesylate.
 37. The solutionof claim 35, wherein the solution comprises from about 1% (w/v) to about4% (w/v) mannitol.
 38. The solution of claim 37, wherein the solutioncomprises 4% (w/v) mannitol.
 39. The solution of claim 35, wherein thealkali metal acetate is sodium acetate.
 40. The solution of claim 35,wherein the solution comprises 3 mM sodium acetate.
 41. The solution ofclaim 35, wherein the solution consists of (i) about 0.25% (w/v) toabout 2% (w/v) of phentolamine mesylate; (ii) about 1% (w/v) to about 6%(w/v) of one or more polyol compounds selected from the group consistingof mannitol, glycerol, and propylene glycol; (iii) about 1 mM to about 6mM of an alkali metal acetate; (iv) acetic acid; and (v) water; whereinthe solution has a pH in the range of 4.5 to 5.5.
 42. An aqueousophthalmic solution free of a chelating agent, comprising: a. about0.25% (w/v) to about 2% (w/v) of phentolamine mesylate; b. about 3%(w/v) to about 5% (w/v) of mannitol; c. about 2 mM to about 4 mM ofsodium acetate; and d. water; wherein the solution has a pH in the rangeof 4.5 to 5.2 and does not contain a chelating agent.
 43. An aqueousophthalmic solution free of a chelating agent, comprising: a. about 0.5%(w/v) to about 1% (w/v) of phentolamine mesylate; b. about 4% mannitol;c. about 3 mM sodium acetate; and d. water; wherein the solution has apH in the range of 4.6 to 5.2 and does not contain a chelating agent.44. The solution of claim 43, wherein less than 2% of the phentolamineor pharmaceutically acceptable salt thereof degrades upon storage at 25°C. for 12 weeks.
 45. The solution of claim 43, wherein less than 2% ofthe phentolamine or pharmaceutically acceptable salt thereof degradesupon storage at 25° C. for 24 weeks.
 46. The solution of claim 43,wherein less than 7% of the phentolamine or pharmaceutically acceptablesalt thereof degrades upon storage at 40° C. for 12 weeks.
 47. A methodof improving visual performance in a patient, comprising administeringto the eye of a patient in need thereof an effective amount of anaqueous ophthalmic solution of claim 1 to improve visual performance inthe patient.
 48. The method of claim 47, wherein the improvement invisual performance is improved visual acuity. 49-51. (canceled)
 52. Themethod of claim 47, wherein the improvement in visual performance isimproved contrast sensitivity.
 53. (canceled)
 54. The method of claim47, wherein the improvement in visual performance is improved contrastsensitivity under mesopic conditions.
 55. (canceled)
 56. A method ofreducing pupil diameter in a patient, comprising administering to theeye of a patient in need thereof an effective amount of an aqueousophthalmic solution of claim 1 to reduce pupil diameter in a patient.57-61. (canceled)
 62. A method of reducing an aberrant focus ofscattered light rays in a patient's eye, comprising administering to theeye of a patient in need thereof an effective amount of an aqueousophthalmic solution of claim 1 to reduce aberrant focus of scatteredlight rays in the patient's eye.
 63. The method of claim 47, wherein theaqueous ophthalmic solution is administered at the bedtime of thepatient. 64-65. (canceled)
 66. The method of claim 47, wherein thepatient is a human.